dve-1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	IBA GO_REF:0000033	ACCEPT	Summary: DVE-1 is a homeodomain-containing transcription factor that regulates RNA polymerase II-dependent transcription of UPR-mt target genes (hsp-6, hsp-60) and thousands of additional genes. The SATB-like domain structure and experimental evidence from reporter assays support this annotation. Reason: The IBA annotation is well-supported by experimental evidence. DVE-1 contains two homeobox DNA-binding domains (UniProt features) and functions as a transcription factor that directly regulates gene expression. PMID:17925224 demonstrates DVE-1 binds to promoters of mitochondrial chaperone genes and is required for their transcriptional activation. PMID:35021096 shows DVE-1 binds to the nhr-80 promoter to transactivate its expression. The phylogenetic inference from SATB family members is consistent with experimental findings. Supporting Evidence: PMID:17925224 Unfolded protein stress in the mitochondria correlates with complex formation between a homeodomain-containing transcription factor DVE-1 and the small ubiquitin-like protein UBL-5 PMID:35021096 The transcription factor DVE-1 binds to the promoter of the nuclear hormone receptor nhr-80 to transactivate its expression
GO:0006357 regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	ACCEPT	Summary: DVE-1 regulates transcription of numerous genes by RNA polymerase II, including UPR-mt target genes and genes involved in lipid metabolism, innate immunity, and longevity. Reason: This IBA annotation is supported by extensive experimental evidence. DVE-1 is required for transcriptional activation of hsp-6 and hsp-60 reporters under mitochondrial stress (PMID:17925224). RNA-seq analyses show DVE-1 knockdown affects thousands of genes (deep research report cites ~3,177 genes changed by dve-1 RNAi). DVE-1 also activates nhr-80 transcription linking UPR-mt to lipid metabolism (PMID:35021096). Supporting Evidence: PMID:17925224 Unfolded protein stress in the mitochondria correlates with complex formation between a homeodomain-containing transcription factor DVE-1 and the small ubiquitin-like protein UBL-5 PMID:35021096 Inactivation of DVE-1 or NHR-80 fully abolishes the citrate-induced lipid accumulation
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA GO_REF:0000033	ACCEPT	Summary: DVE-1 contains two homeobox DNA-binding domains and binds to promoter regions of target genes including mitochondrial chaperone genes and nhr-80. Reason: The IBA annotation is consistent with DVE-1's domain structure (two homeobox domains, SATB-like features) and experimental evidence showing DVE-1 binds to promoters of UPR-mt genes (PMID:17925224) and the nhr-80 promoter (PMID:35021096). While a specific consensus DNA binding motif has not been definitively established, the promoter binding activity supports sequence-specific DNA binding. Supporting Evidence: PMID:17925224 Activation of the UPR(mt) correlates temporally and spatially with nuclear redistribution of DVE-1 and with its enhanced binding to the promoters of mitochondrial chaperone genes PMID:35021096 The transcription factor DVE-1 binds to the promoter of the nuclear hormone receptor nhr-80 to transactivate its expression
GO:0006338 chromatin remodeling	IBA GO_REF:0000033	ACCEPT	Summary: DVE-1 participates in chromatin remodeling as part of the UPR-mt response. It associates with the NuRD chromatin remodeling complex and cooperates with chromatin modifiers to enable stress-responsive gene expression. Reason: DVE-1 functions within a chromatin reorganization hub during mitochondrial stress. PMID:32789178 shows DVE-1 associates with the NuRD complex via LIN-40, mediating chromatin remodeling in response to acetyl-CoA levels. PMID:32934238 demonstrates DVE-1 interacts with HDA-1 to regulate chromatin state for UPR-mt gene expression. The SATB family homology further supports genome-organizing functions. Supporting Evidence: PMID:32789178 NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level PMID:32934238 HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes
GO:0003677 DNA binding	IEA GO_REF:0000120	ACCEPT	Summary: DVE-1 contains two homeobox DNA-binding domains and binds DNA at promoter regions of target genes. Reason: This IEA annotation is correctly inferred from DVE-1's domain architecture. The protein contains two homeobox domains (UniProt FT DNA_BIND 179-248 and 385-458) which are well-characterized DNA-binding domains. Experimental evidence confirms DVE-1 binds to promoters of mitochondrial chaperone genes (PMID:17925224) and nhr-80 (PMID:35021096). The more specific term GO:0000978 is also annotated. Supporting Evidence: PMID:17925224 Activation of the UPR(mt) correlates temporally and spatially with nuclear redistribution of DVE-1 and with its enhanced binding to the promoters of mitochondrial chaperone genes
GO:0003700 DNA-binding transcription factor activity	IEA GO_REF:0000117	ACCEPT	Summary: DVE-1 functions as a DNA-binding transcription factor that regulates expression of UPR-mt genes and many other targets. Reason: This IEA annotation is accurate and supported by experimental evidence. DVE-1 contains homeobox DNA-binding domains and directly activates transcription of target genes. PMID:35021096 explicitly identifies DVE-1 as a transcription factor that transactivates nhr-80 expression. The more specific term GO:0000981 (RNA polymerase II-specific) is also appropriately annotated. Supporting Evidence: PMID:35021096 The transcription factor DVE-1 binds to the promoter of the nuclear hormone receptor nhr-80 to transactivate its expression
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: DVE-1 localizes to the nucleus, particularly under mitochondrial stress conditions when it translocates from cytosol to nucleus. Reason: Nuclear localization of DVE-1 is well-established by multiple experimental studies using DVE-1::GFP reporters. PMID:17925224, PMID:30642431, PMID:32934238, and PMID:32789178 all demonstrate nuclear localization. The IEA inference is correct, though this annotation is superseded by IDA evidence from multiple publications. Supporting Evidence: PMID:17925224 Activation of the UPR(mt) correlates temporally and spatially with nuclear redistribution of DVE-1 and with its enhanced binding to the promoters of mitochondrial chaperone genes
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: DVE-1 is found in the cytosol under basal conditions and translocates to the nucleus upon mitochondrial stress. SUMOylation at K327 retains DVE-1 in cytosol. Reason: Cytosolic localization is supported by experimental evidence. PMID:30642431 demonstrates that SUMOylated DVE-1 localizes to the cytosol, and desumoylation by ULP-4 is required for nuclear accumulation during mitochondrial stress. UniProt notes that DVE-1 translocates from cytosol to nucleus upon mitochondrial stress. Supporting Evidence: PMID:30642431 Conversely, SUMO-mimetic DVE-1 constitutively localized in the cytosol (Figure 3G)
GO:0006338 chromatin remodeling	IEA GO_REF:0000002	ACCEPT	Summary: DVE-1 participates in chromatin remodeling via interaction with NuRD complex and HDA-1. Reason: This IEA annotation (from InterPro) is consistent with DVE-1's SATB-like domain structure and experimental evidence. DVE-1 associates with the NuRD chromatin remodeling complex (PMID:32789178) and cooperates with HDA-1 (PMID:32934238) to regulate chromatin state. Duplicate with IBA annotation above but both are acceptable given different evidence sources. Supporting Evidence: PMID:32789178 NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level
GO:0006357 regulation of transcription by RNA polymerase II	IEA GO_REF:0000117	ACCEPT	Summary: DVE-1 regulates RNA polymerase II-dependent transcription of many genes. Reason: This IEA annotation is accurate. DVE-1 regulates transcription of UPR-mt target genes and thousands of additional genes. This is a duplicate of the IBA annotation but from a different evidence source. Both are acceptable. Supporting Evidence: PMID:17925224 Unfolded protein stress in the mitochondria correlates with complex formation between a homeodomain-containing transcription factor DVE-1 and the small ubiquitin-like protein UBL-5
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000108	ACCEPT	Summary: DVE-1 positively regulates transcription of UPR-mt target genes including hsp-6, hsp-60, and nhr-80. Reason: This annotation is well-supported. DVE-1 functions as a transcriptional activator for mitochondrial chaperone genes during UPR-mt (PMID:17925224) and for nhr-80 in lipid metabolism (PMID:35021096). The IDA annotation for GO:0001228 (DNA-binding transcription activator activity) provides direct experimental support for this role. Supporting Evidence: PMID:35021096 The transcription factor DVE-1 binds to the promoter of the nuclear hormone receptor nhr-80 to transactivate its expression
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific	IDA PMID:35021096 NHR-80 senses the mitochondrial UPR to rewire citrate metabo...	ACCEPT	Summary: DVE-1 functions as a transcriptional activator, directly binding to the nhr-80 promoter and transactivating its expression in response to citrate-induced UPR-mt. Reason: This IDA annotation from PMID:35021096 is directly supported by experimental evidence showing DVE-1 binds to and transactivates the nhr-80 promoter. The study demonstrates the DVE-1-NHR-80-lipogenesis axis linking mitochondrial stress to lipid metabolism. Inactivation of DVE-1 abolishes citrate-induced lipid accumulation. Supporting Evidence: PMID:35021096 The transcription factor DVE-1 binds to the promoter of the nuclear hormone receptor nhr-80 to transactivate its expression
GO:0045088 regulation of innate immune response	IMP PMID:32934238 Histone deacetylase HDA-1 modulates mitochondrial stress res...	ACCEPT	Summary: DVE-1 is required for UPR-mt-mediated innate immune responses, including survival against pathogen challenge. Reason: PMID:32934238 demonstrates that dve-1 RNAi suppresses activation of immune response genes and reduces survival when animals are challenged with pathogens (Pseudomonas, Rhodococcus) under mitochondrial stress conditions. DVE-1 cooperates with HDA-1 to induce transcription of innate immune response genes. Supporting Evidence: PMID:32934238 hda-1 or dve-1 RNAi also suppressed the activation of the immune response and reduced the survival rate when the animals were challenged with another mitochondrial insult, a Rhodococcus strain isolated from the natural habitat of C. elegans
GO:0000785 chromatin	IDA PMID:32934238 Histone deacetylase HDA-1 modulates mitochondrial stress res...	ACCEPT	Summary: DVE-1 associates with chromatin where it functions as a genome organizer coordinating with HDA-1 and the NuRD complex. Reason: PMID:32934238 describes DVE-1 as a "genome organizer" that coordinates with HDA-1 at chromatin to regulate gene expression. PMID:32789178 shows DVE-1 associates with the NuRD complex. DVE-1 binds to promoter chromatin of target genes. The SATB family homology further supports chromatin association. Supporting Evidence: PMID:32934238 HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes
GO:0005634 nucleus	IDA PMID:32934238 Histone deacetylase HDA-1 modulates mitochondrial stress res...	ACCEPT	Summary: DVE-1::GFP accumulates in the nucleus under mitochondrial stress conditions. Reason: PMID:32934238 uses DVE-1::GFP reporter to demonstrate nuclear localization. Multiple other publications (PMID:17925224, PMID:30642431, PMID:32789178) confirm nuclear localization of DVE-1 during mitochondrial stress using similar approaches. Supporting Evidence: PMID:32934238 HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes
GO:0019899 enzyme binding	IPI PMID:30642431 SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated in...	ACCEPT	Summary: DVE-1 interacts with the SUMO peptidase ULP-4, which desumoylates DVE-1 at K327 to allow nuclear accumulation during UPR-mt. Reason: DVE-1 interacts with ULP-4 (PMID:30642431), a SUMO peptidase enzyme. ULP-4 is an enzyme and DVE-1 is its substrate, so enzyme binding accurately describes this interaction. The interaction is functionally important for regulating DVE-1 localization during mitochondrial stress. Supporting Evidence: PMID:30642431 DVE-1 interacts with ULP-4 and SMO-1 in yeast two-hybrid assay
GO:0019899 enzyme binding	IPI PMID:32934238 Histone deacetylase HDA-1 modulates mitochondrial stress res...	ACCEPT	Summary: DVE-1 interacts with HDA-1 (histone deacetylase), an enzyme that modifies chromatin. Reason: PMID:32934238 demonstrates that DVE-1 interacts with HDA-1, the C. elegans ortholog of mammalian HDAC1/2. HDA-1 is a histone deacetylase enzyme. The interaction coordinates chromatin regulation for UPR-mt gene expression. "Enzyme binding" accurately describes this interaction. Supporting Evidence: PMID:32934238 HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes
GO:0034514 mitochondrial unfolded protein response	IMP PMID:30642431 SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated in...	ACCEPT	Summary: DVE-1 is essential for the mitochondrial unfolded protein response. SUMOylation regulates DVE-1 localization during UPR-mt activation. Reason: PMID:30642431 demonstrates that ULP-4-mediated desumoylation of DVE-1 is required for UPR-mt activation. DVE-1 is one of two key transcription factors (along with ATFS-1) governing the UPR-mt transcriptional program. dve-1 RNAi attenuates hsp-6/hsp-60 reporter induction. Supporting Evidence: PMID:30642431 during mitochondrial stress, ULP-4 deSUMOylates DVE-1 at K327 residue to allow its nuclear accumulation to initiate UPRmt
GO:0044877 protein-containing complex binding	IDA PMID:32789178 NuRD mediates mitochondrial stress-induced longevity via chr...	ACCEPT	Summary: DVE-1 associates with the NuRD (Nucleosome Remodeling and Deacetylase) complex via interaction with LIN-40. Reason: PMID:32789178 demonstrates DVE-1 interacts with LIN-40 and associates with the NuRD complex. This interaction mediates chromatin remodeling in response to mitochondrial stress and acetyl-CoA levels. The annotation accurately reflects DVE-1's binding to this multi-protein complex. Supporting Evidence: PMID:32789178 NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level
GO:0005515 protein binding	IPI PMID:32789178 NuRD mediates mitochondrial stress-induced longevity via chr...	MARK AS OVER ANNOTATED	Summary: DVE-1 interacts with LIN-40, a component of the NuRD complex. Reason: While DVE-1 does interact with LIN-40 (PMID:32789178), "protein binding" is too generic and uninformative. The more specific annotation GO:0044877 "protein-containing complex binding" from the same publication better captures this interaction. GO guidelines recommend avoiding generic "protein binding" when more specific terms apply. Supporting Evidence: PMID:32789178 NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level
GO:0005634 nucleus	IDA PMID:30642431 SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated in...	ACCEPT	Summary: DVE-1 localizes to nucleus upon mitochondrial stress after desumoylation by ULP-4. Reason: PMID:30642431 uses DVE-1::GFP imaging to demonstrate nuclear localization. The study shows that desumoylation at K327 is required for nuclear accumulation during mitochondrial stress. DVE-1 K327R (non-SUMOylatable) constitutively localizes to the nucleus. Supporting Evidence: PMID:30642431 DVE-1 K327R constitutively localized in the nucleus of C. elegans, even if ulp-4 was knocked down by RNAi (Figure 3F)
GO:0005634 nucleus	IDA PMID:32789178 NuRD mediates mitochondrial stress-induced longevity via chr...	ACCEPT	Summary: DVE-1::GFP shows nuclear localization in response to mitochondrial stress. Reason: PMID:32789178 demonstrates nuclear accumulation of DVE-1::GFP under mitochondrial stress conditions using fluorescence microscopy. This is consistent with other publications. Duplicate annotations with different references are acceptable. Supporting Evidence: PMID:32789178 NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level
GO:0005829 cytosol	IDA PMID:30642431 SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated in...	ACCEPT	Summary: SUMOylated DVE-1 localizes to the cytosol. Desumoylation by ULP-4 allows nuclear translocation. Reason: PMID:30642431 directly demonstrates that SUMOylation at K327 retains DVE-1 in the cytosol. A SUMO-mimetic DVE-1 fusion constitutively localizes to the cytosol. This provides direct evidence for cytosolic localization under specific conditions. Supporting Evidence: PMID:30642431 Conversely, SUMO-mimetic DVE-1 constitutively localized in the cytosol (Figure 3G)
GO:0005829 cytosol	IDA PMID:32789178 NuRD mediates mitochondrial stress-induced longevity via chr...	ACCEPT	Summary: DVE-1 can be found in the cytosol, consistent with its stress-induced translocation from cytosol to nucleus. Reason: PMID:32789178 studies DVE-1::GFP localization dynamics. The cytosolic pool of DVE-1 translocates to nucleus upon mitochondrial stress. UniProt annotates cytosol based on this evidence. Supporting Evidence: PMID:32789178 NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level
GO:0034514 mitochondrial unfolded protein response	IMP PMID:30057120 The Mitochondrial Unfolded Protein Response Is Mediated Cell...	ACCEPT	Summary: DVE-1 functions in cell-non-autonomous UPR-mt signaling mediated by Wnt signaling. Reason: PMID:30057120 examines cell-non-autonomous UPR-mt signaling via Wnt pathway. DVE-1 is a known component of the UPR-mt transcriptional program activated downstream of this signaling. The publication expands understanding of how UPR-mt is coordinated across tissues. Supporting Evidence: PMID:30057120 The mitochondrial unfolded protein response (UPRmt) can be triggered in a cell-non-autonomous fashion
GO:0034514 mitochondrial unfolded protein response	IMP PMID:17925224 ClpP mediates activation of a mitochondrial unfolded protein...	ACCEPT	Summary: DVE-1 was identified as a key regulator of UPR-mt in the foundational genome-wide RNAi screen. Required for activation of mitochondrial chaperone gene expression. Reason: PMID:17925224 is the seminal publication identifying DVE-1's role in UPR-mt. A genome-wide RNAi screen identified dve-1 as required for UPR-mt signaling. DVE-1 forms a complex with UBL-5, redistributes to nucleus, and binds to promoters of mitochondrial chaperone genes under stress. Supporting Evidence: PMID:17925224 Unfolded protein stress in the mitochondria correlates with complex formation between a homeodomain-containing transcription factor DVE-1 and the small ubiquitin-like protein UBL-5, both of which are encoded by genes required for signaling the UPR(mt)
GO:0005667 transcription regulator complex	IPI PMID:17925224 ClpP mediates activation of a mitochondrial unfolded protein...	ACCEPT	Summary: DVE-1 forms a complex with UBL-5 to regulate UPR-mt gene transcription. This complex forms specifically under mitochondrial stress conditions. Reason: PMID:17925224 demonstrates that DVE-1 and UBL-5 form a complex in a mitochondrial stress-dependent manner. This DVE-1/UBL-5 complex is required for transcriptional regulation of UPR-mt target genes. UniProt confirms the interaction. Supporting Evidence: PMID:17925224 Unfolded protein stress in the mitochondria correlates with complex formation between a homeodomain-containing transcription factor DVE-1 and the small ubiquitin-like protein UBL-5
GO:0051087 protein-folding chaperone binding	IPI PMID:17925224 ClpP mediates activation of a mitochondrial unfolded protein...	UNDECIDED	Summary: DVE-1 interacts with UBL-5, which has chaperone-like properties and is part of the UPR-mt regulatory complex. Reason: While DVE-1 interacts with UBL-5, it is unclear whether UBL-5 functions as a protein-folding chaperone. UBL-5 is a small ubiquitin-like protein that forms a complex with DVE-1 during mitochondrial stress, but its classification as a chaperone is not well-established. This annotation may be based on interpretation of UBL-5 function that requires further validation. Supporting Evidence: PMID:17925224 Unfolded protein stress in the mitochondria correlates with complex formation between a homeodomain-containing transcription factor DVE-1 and the small ubiquitin-like protein UBL-5
GO:0005634 nucleus	IDA PMID:17925224 ClpP mediates activation of a mitochondrial unfolded protein...	ACCEPT	Summary: DVE-1 redistributes to the nucleus under mitochondrial stress, as shown by the foundational UPR-mt study. Reason: PMID:17925224 demonstrates nuclear redistribution of DVE-1 correlates with UPR-mt activation. This is the original publication establishing DVE-1 nuclear localization during mitochondrial stress. Supporting Evidence: PMID:17925224 Activation of the UPR(mt) correlates temporally and spatially with nuclear redistribution of DVE-1 and with its enhanced binding to the promoters of mitochondrial chaperone genes
GO:0009792 embryo development ending in birth or egg hatching	IMP PMID:17925224 ClpP mediates activation of a mitochondrial unfolded protein...	KEEP AS NON CORE	Summary: DVE-1 is essential for embryonic development. Null alleles are embryonic lethal. Reason: PMID:17925224 and UniProt note that dve-1 is required for embryonic development (null alleles are lethal). However, this is likely a consequence of DVE-1's essential role in transcriptional regulation and chromatin organization rather than a specific developmental function. The core function is as a UPR-mt transcriptional regulator and chromatin organizer. Supporting Evidence: file:worm/dve-1/dve-1-deep-research-falcon.md DVE-1 is required for embryonic development PMID:17925224 ClpP mediates activation of a mitochondrial unfolded protein response in C.

Core Functions

DVE-1 is one of two key transcription factors (with ATFS-1) governing the UPR-mt transcriptional program. Identified in foundational genome-wide RNAi screen (PMID:17925224). Forms complex with UBL-5 under stress. Required for induction of mitochondrial chaperone genes hsp-6 and hsp-60. Nuclear localization regulated by SUMOylation/desumoylation (PMID:30642431). Coordinates with chromatin modifiers HDA-1 (PMID:32934238) and NuRD complex (PMID:32789178).

Molecular Function:

DNA-binding transcription activator activity, RNA polymerase II-specific

Directly Involved In:

mitochondrial unfolded protein response

Cellular Locations:

nucleus

DVE-1 functions as a chromatin-associated genome organizer. Associates with NuRD complex via LIN-40 (PMID:32789178). Coordinates with HDA-1 histone deacetylase (PMID:32934238). SATB family homology supports roles in higher-order chromatin organization. Chromatin reorganization is required for UPR-mt gene accessibility and longevity phenotypes.

Molecular Function:

DNA-binding transcription factor activity, RNA polymerase II-specific

Directly Involved In:

chromatin remodeling

Cellular Locations:

chromatin

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

DVE-1 contains homeobox domains and SATB-like features that predict DNA binding and chromatin organization functions.

GO_REF:0000033

Annotation inferences using phylogenetic trees

DVE-1 is orthologous to Drosophila Dve and mammalian SATB1/SATB2, supporting transcription factor and chromatin organization functions.

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

DVE-1 localizes to both cytosol and nucleus depending on stress state.

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on inter-ontology links

Positive regulation of transcription inferred from activator activity annotations.

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

Transcription factor activity correctly predicted from domain structure.

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

DNA binding and nuclear localization correctly inferred from homeobox domains.

PMID:17925224

ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans.

Identified DVE-1 as essential for UPR-mt signaling via genome-wide RNAi screen.

"Unfolded protein stress in the mitochondria correlates with complex formation between a homeodomain-containing transcription factor DVE-1 and the small ubiquitin-like protein UBL-5, both of which are encoded by genes required for signaling the UPR(mt)"
DVE-1 forms stress-dependent complex with UBL-5.

"Unfolded protein stress in the mitochondria correlates with complex formation between a homeodomain-containing transcription factor DVE-1 and the small ubiquitin-like protein UBL-5"
DVE-1 redistributes to nucleus and binds promoters of mitochondrial chaperone genes under stress.

"Activation of the UPR(mt) correlates temporally and spatially with nuclear redistribution of DVE-1 and with its enhanced binding to the promoters of mitochondrial chaperone genes"

PMID:30057120

The Mitochondrial Unfolded Protein Response Is Mediated Cell-Non-autonomously by Retromer-Dependent Wnt Signaling.

UPR-mt can be triggered cell-non-autonomously via Wnt signaling from neurons to peripheral tissues.
DVE-1 functions in downstream transcriptional response to these signals.

PMID:30642431

SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated innate immunity and lifespan extension.

ULP-4 desumoylates DVE-1 at K327 to enable nuclear accumulation during UPR-mt.

"during mitochondrial stress, ULP-4 deSUMOylates DVE-1 at K327 residue to allow its nuclear accumulation to initiate UPRmt"
SUMOylated DVE-1 is retained in cytosol.

"Conversely, SUMO-mimetic DVE-1 constitutively localized in the cytosol (Figure 3G)"
DVE-1 interacts with ULP-4 and SMO-1 (SUMO).

"DVE-1 interacts with ULP-4 and SMO-1 in yeast two-hybrid assay"

PMID:32789178

NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level.

DVE-1 associates with NuRD complex via LIN-40.

"NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level"
Acetyl-CoA levels regulate chromatin remodeling and NuRD/DVE-1 nuclear accumulation.

"NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level"

PMID:32934238

Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity.

HDA-1 interacts and coordinates with DVE-1 genome organizer.

"HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes"
Together they induce transcription of UPR-mt, innate immune, and metabolic genes.

"HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes"
dve-1 RNAi suppresses immune response and survival against pathogens.

"hda-1 or dve-1 RNAi also suppressed the activation of the immune response and reduced the survival rate when the animals were challenged with another mitochondrial insult, a Rhodococcus strain isolated from the natural habitat of C. elegans"

PMID:35021096

NHR-80 senses the mitochondrial UPR to rewire citrate metabolism for lipid accumulation in Caenorhabditis elegans.

DVE-1 binds to nhr-80 promoter and transactivates its expression.

"The transcription factor DVE-1 binds to the promoter of the nuclear hormone receptor nhr-80 to transactivate its expression"
DVE-1-NHR-80 axis links UPR-mt to lipid metabolism.

"our work uncovers a DVE-1-NHR-80-lipogenesis axis linking the transmission of the mitochondrial stress signal to lipid metabolism"
Inactivation of DVE-1 abolishes citrate-induced lipid accumulation.

"Inactivation of DVE-1 or NHR-80 fully abolishes the citrate-induced lipid accumulation"

file:worm/dve-1/dve-1-deep-research-falcon.md

Deep research on DVE-1 function

DVE-1 regulates thousands of genes including those involved in lipid metabolism, innate immunity, and longevity.
DVE-1 functions as a chromatin organizer similar to mammalian SATB family proteins.
DVE-1 is required for embryonic development.

Suggested Experiments

Experiment: ChIP-seq for DVE-1 to comprehensively map genomic binding sites and identify consensus motif.

Hypothesis: DVE-1 binds to a specific DNA motif at promoters of UPR-mt target genes.

Experiment: Structure-function analysis of individual homeobox domains to determine their contributions.

Hypothesis: The two homeobox domains have distinct or cooperative roles in DNA binding.

Experiment: Time-resolved proteomics of DVE-1 complexes under different stress conditions.

Hypothesis: DVE-1 forms distinct protein complexes under different physiological conditions.

Experiment: Single-cell analysis of DVE-1 activity across tissues during UPR-mt.

Hypothesis: DVE-1 activation varies across cell types during systemic mitochondrial stress.

Deep Research

Falcon

(dve-1-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 18 citations 2025-12-28T11:01:25.940115

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research plan and verification
We verified the target as Caenorhabditis elegans dve-1, a homeodomain transcriptional regulator homologous to Drosophila defective proventriculus (Dve) and mammalian SATB family proteins. DVE-1 functions in the mitochondrial unfolded protein response (UPRmt) and additional programs affecting neuronal remodeling and longevity, consistent with a nuclear, chromatin-associated transcription factor. This matches the provided identity (UniProt Q86MI0; homeodomain/SATB-like features). Foundational primary sources in C. elegans confirm dve-1’s role in UPRmt and its interaction with UBL-5; more recent studies (2023–2024) uncover roles in synapse elimination and longevity that are partly independent of canonical UPRmt activation (haynes2007clppmediatesactivation pages 1-2, tian2016mitochondrialstressinduces pages 9-11, alexander2023thehomeodomaintranscriptional pages 2-4, sheng2024amitochondrialunfolded pages 8-10, sheng2024amitochondrialunfolded pages 10-11, sheng2024amitochondrialunfolded pages 6-8, haynes2022mitochondrialdysfunctionaging pages 6-7).

Key concepts and definitions with current understanding
- DVE-1: a C. elegans homeodomain transcriptional regulator, orthologous to Drosophila Dve/SATB-like proteins. It is essential (null lethal), acts at chromatin, and is required for robust induction of UPRmt genes upon mitochondrial stress (e.g., hsp-6/hsp-60 reporters). DVE-1 forms a complex with UBL-5 and cooperates with chromatin modifiers (LIN-65, MET-2) to enable stress-responsive transcription (Haynes et al., Dev Cell, 2007; Tian et al., Cell, 2016; Genetics review, 2022). URLs: https://doi.org/10.1016/j.devcel.2007.07.016 (Oct 2007); https://doi.org/10.1016/j.cell.2016.04.011 (May 2016); https://doi.org/10.1093/genetics/iyac160 (Nov 2022) (haynes2007clppmediatesactivation pages 1-2, tian2016mitochondrialstressinduces pages 9-11, haynes2022mitochondrialdysfunctionaging pages 6-7).
- UPRmt: a mitochondria-to-nucleus stress signaling pathway that induces mitochondrial chaperones/proteases and broader metabolic programs; in C. elegans, ATFS-1 and DVE-1/UBL-5 act in parallel/coordinate branches. ATFS-1 is normally imported into mitochondria and degraded, but under stress accumulates in the nucleus; DVE-1 operates at chromatin, enabling transcription in an ATFS-1–coordinated manner. Chromatin remodeling (e.g., JMJD demethylases, CBP-1 HAT, MET-2 H3K9me2, LIN-65) is required to open chromatin for DVE-1/ATFS-1 binding; DVE-1 and ATFS-1 activities are also modulated by SUMO/ULP-4 (Genetics 2022; Cell 2016). URLs: above; https://doi.org/10.1093/genetics/iyac160 (Nov 2022) (haynes2022mitochondrialdysfunctionaging pages 6-7, tian2016mitochondrialstressinduces pages 9-11).
- Cellular localization: DVE-1 is nuclear under stress and accumulates to promoters of UPRmt target genes; its nuclear localization and protein stability are interdependent with LIN-65 and depend on MET-2/H3K9me2 during stress (Cell 2016). Imaging of a DVE-1::GFP translational reporter confirms stress-induced nuclear localization; in certain ciliary mutants (daf-10), nuclear DVE-1 decreases while cytosolic puncta increase (Cell Reports 2024). URLs: https://doi.org/10.1016/j.cell.2016.04.011 (May 2016); https://doi.org/10.1016/j.celrep.2024.114889 (Nov 2024) (tian2016mitochondrialstressinduces pages 9-11, sheng2024amitochondrialunfolded pages 6-8).

Recent developments and latest research (prioritize 2023–2024)
- Neuronal circuit remodeling (Nature Communications 2023): DVE-1 directs synapse elimination during developmental remodeling of GABAergic DD motor neurons. Hypomorphic mutations in the DVE-1 homeodomain (e.g., uf171 P→S; tm4803 deleting helix III) cause persistent dorsal acetylcholine receptor clusters and apposing presynaptic sites that normally are removed by ~22 h after hatching, persisting into late L4 (>40 h). GABAergic cell-autonomous expression of wild-type dve-1 rescues the elimination defect; overexpression in wild type has little effect. Methods: forward genetic screen, WGS, confocal imaging, conditional AID depletion. URL: https://doi.org/10.1038/s41467-023-43281-4 (Nov 2023) (alexander2023thehomeodomaintranscriptional pages 2-4).
- Longevity regulation independent of canonical UPRmt (Cell Reports 2024): DVE-1 modulates lifespan in multiple contexts beyond classical UPRmt activation. Lifespan phenotypes show that dve-1(RNAi) can suppress or enhance longevity depending on background: it largely abolishes dietary restriction (eat-2) longevity and strongly suppresses germline-loss (glp-1) longevity, whereas in isp-1(qm150) mitochondrial mutants dve-1(RNAi) does not shorten and may further extend lifespan; in nuo-6 RNAi, atfs-1(RNAi) strongly suppresses mitoUPR while dve-1(RNAi) has little effect on mitoUPR readouts yet more potently reduces lifespan extension. Transcriptome analyses indicate DVE-1 regulates thousands of genes with minimal overlap with ATFS-1 at rest (3,177 vs 156; nine overlapping), shifting to more activator-like roles in certain long-lived backgrounds. Methods: targeted RNAi screening, lifespan assays, DVE-1::GFP imaging, RNA-seq reanalysis. URL: https://doi.org/10.1016/j.celrep.2024.114889 (Nov 2024) (sheng2024amitochondrialunfolded pages 8-10, sheng2024amitochondrialunfolded pages 10-11, sheng2024amitochondrialunfolded pages 6-8).
- Updated mechanistic context (Genetics 2022 review): DVE-1 binds chromatin with UBL-5 to facilitate ATFS-1–dependent transcription; desumoylation by ULP-4 enables DVE-1 DNA binding; chromatin opening by JMJD-1.2/JMJD-3.1 and CBP-1 precedes/permits DVE-1/ATFS-1 action. URL: https://doi.org/10.1093/genetics/iyac160 (Nov 2022) (haynes2022mitochondrialdysfunctionaging pages 6-7).

Current applications and real-world implementations
- Genetic reporters and stress assays: DVE-1 function is routinely monitored using UPRmt reporters (Phsp-6::GFP, Phsp-60::GFP) in genetic/chemical stress paradigms (e.g., spg-7 RNAi; ethidium bromide), providing practical readouts for mitochondrial proteostasis and for screening modulators of stress responses and longevity (Dev Cell 2007; Cell 2016). URLs: https://doi.org/10.1016/j.devcel.2007.07.016 (Oct 2007); https://doi.org/10.1016/j.cell.2016.04.011 (May 2016) (haynes2007clppmediatesactivation pages 1-2, tian2016mitochondrialstressinduces pages 9-11).
- Neuronal remodeling assays: The 2023 Nature Communications study establishes dve-1 as a lever for probing proteasome/ubiquitin–proteasome regulation in synapse elimination, with tools including neuron-specific expression/repression and AID-based acute depletion, supporting applications in circuit-development studies and screening (Nov 2023). URL: https://doi.org/10.1038/s41467-023-43281-4 (alexander2023thehomeodomaintranscriptional pages 2-4).
- Longevity modulation: The 2024 Cell Reports study indicates that targeting DVE-1 can tune lifespan across models (dietary restriction, germline-loss, mitochondrial mutants), often without canonical UPRmt activation, pointing to wider translational interest in chromatin and proteostasis pathways modulated by DVE-1 (Nov 2024). URL: https://doi.org/10.1016/j.celrep.2024.114889 (sheng2024amitochondrialunfolded pages 8-10, sheng2024amitochondrialunfolded pages 10-11, sheng2024amitochondrialunfolded pages 6-8).

Expert opinions and analysis from authoritative sources
- Mechanistic synthesis (Genetics 2022): DVE-1 is a chromatin-associated factor that partners with UBL-5, with its activity controlled by SUMO/ULP-4 and upstream chromatin-remodeling enzymes (JMJD-1.2/JMJD-3.1; CBP-1). ATFS-1 alone is not sufficient for lifespan extension, suggesting UPRmt activation and longevity are not tightly coupled; DVE-1 adds a chromatin-based regulatory layer that contextualizes stress signaling (Nov 2022). URL: https://doi.org/10.1093/genetics/iyac160 (haynes2022mitochondrialdysfunctionaging pages 6-7).
- Stress–chromatin interface (Cell 2016): DVE-1 and LIN-65 co-accumulate in nuclei under mitochondrial stress, with MET-2–dependent H3K9me2 changes coordinating chromatin reorganization for UPRmt and lifespan phenotypes, indicating DVE-1 functions within a chromatin-remodeling hub integrating mitochondrial cues (May 2016). URL: https://doi.org/10.1016/j.cell.2016.04.011 (tian2016mitochondrialstressinduces pages 9-11).

Relevant statistics and data from recent studies
- Transcriptome scope: DVE-1 regulates substantially more genes than ATFS-1 at baseline (dve-1 RNAi: 3,177 genes; atfs-1 RNAi: 156; nine overlapping). In long-lived backgrounds (e.g., daf-10, eat-2), DVE-1 shifts toward activator roles (e.g., 1,281 up/65 down in daf-10; 3,061/856 in eat-2), with strong overlap with ATFS-1-upregulated targets under those conditions (Cell Reports 2024). URL: https://doi.org/10.1016/j.celrep.2024.114889 (Nov 2024) (sheng2024amitochondrialunfolded pages 10-11).
- Neuronal remodeling timing: In wild-type worms, dorsally localized juvenile iAChR clusters are eliminated by ~22 h post-hatch; in dve-1 hypomorphic mutants they persist beyond 40 h into late L4. Rescue by neuron-specific dve-1 confirms cell-autonomous requirement (Nature Communications 2023). URL: https://doi.org/10.1038/s41467-023-43281-4 (Nov 2023) (alexander2023thehomeodomaintranscriptional pages 2-4).
- Reporter specificity: dve-1(RNAi) reduces induction of mitochondrial UPR reporters (hsp-6/hsp-60) under mitochondrial stress (e.g., spg-7 RNAi, ethidium bromide), without affecting ER UPR reporter (hsp-4::GFP) induced by tunicamycin, indicating pathway specificity (Dev Cell 2007). URL: https://doi.org/10.1016/j.devcel.2007.07.016 (Oct 2007) (haynes2007clppmediatesactivation pages 1-2).
- Localization dependencies: Loss of met-2 reduces nuclear H3K9me2 and diminishes DVE-1/LIN-65 nuclear accumulation, lowering UPRmt induction and partially suppressing stress-triggered lifespan extension (Cell 2016). URL: https://doi.org/10.1016/j.cell.2016.04.011 (May 2016) (tian2016mitochondrialstressinduces pages 9-11).

Functional annotation: mechanism, localization, pathways, partners, and methods
- Molecular function: DVE-1 is a nuclear transcriptional regulator acting at chromatin to facilitate UPRmt gene expression in cooperation with UBL-5 and chromatin modifiers; in other contexts it regulates extensive gene networks linked to proteostasis, immunity, GPCRs, and the ubiquitin–proteasome system. It likely functions as both repressor and activator depending on physiological context and genetic background (Cell Reports 2024; Genetics 2022; Cell 2016). URLs: https://doi.org/10.1016/j.celrep.2024.114889 (Nov 2024); https://doi.org/10.1093/genetics/iyac160 (Nov 2022); https://doi.org/10.1016/j.cell.2016.04.011 (May 2016) (sheng2024amitochondrialunfolded pages 8-10, sheng2024amitochondrialunfolded pages 10-11, haynes2022mitochondrialdysfunctionaging pages 6-7, tian2016mitochondrialstressinduces pages 9-11).
- Cellular localization: Predominantly nuclear under mitochondrial stress; nuclear accumulation interdependent with LIN-65 and sensitive to MET-2/H3K9me2 state. In certain noncanonical longevity contexts (e.g., daf-10), DVE-1 nuclear levels decrease while cytosolic puncta increase; deletion of a predicted NLS disperses DVE-1 but both WT and ΔNLS overexpression can extend lifespan, suggesting nuclear and extra-nuclear pools can contribute to organismal phenotypes (Cell 2016; Cell Reports 2024). URLs: as above (tian2016mitochondrialstressinduces pages 9-11, sheng2024amitochondrialunfolded pages 6-8).
- Pathway membership: Canonical UPRmt branch with UBL-5, acting in parallel/coordination with ATFS-1, downstream of mitochondrial proteostasis perturbations (e.g., CLPP-1/ClpP activity). DVE-1 is required for induction of mitochondrial chaperones/proteases (hsp-6/hsp-60). Chromatin remodeling is an upstream permissive layer (Dev Cell 2007; Cell 2016; Genetics 2022). URLs: above (haynes2007clppmediatesactivation pages 1-2, tian2016mitochondrialstressinduces pages 9-11, haynes2022mitochondrialdysfunctionaging pages 6-7).
- Key partners: UBL-5 (complex with DVE-1), LIN-65 and MET-2 (chromatin reorganization/nuclear localization), ATFS-1 (parallel transcriptional regulator), with regulation by SUMO/ULP-4 and histone modifiers (JMJD-1.2/JMJD-3.1; CBP-1) (Genetics 2022; Dev Cell 2007; Cell 2016). URLs: above (haynes2022mitochondrialdysfunctionaging pages 6-7, haynes2007clppmediatesactivation pages 1-2, tian2016mitochondrialstressinduces pages 9-11).
- DNA recognition: DVE-1 binds chromatin at UPRmt gene promoters, but no single short consensus DNA motif is firmly established in the cited experimental excerpts; its SATB-like homology suggests roles as a genome organizer influencing accessibility and promoter architecture (Cell 2016; Genetics 2022). URLs: above (tian2016mitochondrialstressinduces pages 9-11, haynes2022mitochondrialdysfunctionaging pages 6-7).
- Methods establishing function: genome-scale and targeted RNAi screens; hsp-6/hsp-60 reporter assays; confocal imaging of DVE-1::GFP; lifespan assays across genetic/physiological backgrounds; forward genetic identification of homeodomain mutations; conditional AID depletion; RNA-seq reanalyses (Dev Cell 2007; Cell 2016; Nat Commun 2023; Cell Reports 2024). URLs: above (haynes2007clppmediatesactivation pages 1-2, tian2016mitochondrialstressinduces pages 9-11, alexander2023thehomeodomaintranscriptional pages 2-4, sheng2024amitochondrialunfolded pages 8-10, sheng2024amitochondrialunfolded pages 10-11, sheng2024amitochondrialunfolded pages 6-8).

Concise summary table
| Category | Key points | Evidence / notes | Source |
|---|---|---|---|
| Identity | - Gene: dve-1
- Organism: Caenorhabditis elegans
- UniProt: Q86MI0 | DVE-1 originally characterized as the C. elegans homolog of Drosophila Dve / SATB-family; essential gene (null lethal). (haynes2007clppmediatesactivation pages 1-2, haynes2022mitochondrialdysfunctionaging pages 6-7) | Haynes et al., Dev Cell – https://doi.org/10.1016/j.devcel.2007.07.016 (2007); Haynes & Hekimi, Genetics – https://doi.org/10.1093/genetics/iyac160 (2022) |
| Domains / family | - Homeodomain (HD)
- SATB-like / genome-organizer homology
- ULD / SATB_ULD-like features reported in annotation | Domain and SATB-family homology reported; homeodomain underpins DNA/chromatin association. (haynes2007clppmediatesactivation pages 1-2, sheng2024amitochondrialunfolded pages 3-5) | UniProt Q86MI0 annotation; Haynes et al., 2007 (2007) |
| Primary functions | - Transcriptional regulator of mitochondrial stress response (UPRmt)
- Chromatin reorganization / genome-organization roles
- Additional transcriptional programs affecting longevity and synapse remodeling | DVE-1 acts with chromatin remodelers to permit UPRmt gene induction and also controls non-UPRmt gene networks affecting lifespan and synapse elimination. (tian2016mitochondrialstressinduces pages 9-11, sheng2024amitochondrialunfolded pages 6-8, sheng2024amitochondrialunfolded pages 8-10) | Tian et al., Cell – https://doi.org/10.1016/j.cell.2016.04.011 (2016); Sheng et al., Cell Reports – https://doi.org/10.1016/j.celrep.2024.114889 (2024) |
| Pathways (notably UPRmt) | - Required for robust induction of canonical UPRmt reporters (hsp-60, hsp-6)
- Works in parallel with ATFS-1 and with UBL-5 / chromatin modifiers (MET-2, LIN-65) | Genetic and RNAi experiments show dve-1(RNAi) attenuates hsp-60/hsp-6 reporter induction; chromatin modifiers control DVE-1 nuclear accumulation and UPRmt responsiveness. (haynes2007clppmediatesactivation pages 1-2, tian2016mitochondrialstressinduces pages 9-11, haynes2022mitochondrialdysfunctionaging pages 6-7) | Haynes et al., 2007 (2007); Tian et al., 2016 (2016) |
| Cellular localization | - Predominantly nuclear under mitochondrial stress
- Nuclear accumulation dependent on chromatin-remodeling factors; can show cytosolic puncta in some mutants | Imaging of DVE-1::GFP shows stress-induced nuclear relocalization; daf-10 ciliary mutants alter nuclear/cytosolic distribution. (sheng2024amitochondrialunfolded pages 6-8, tian2016mitochondrialstressinduces pages 9-11, alexander2023thehomeodomaintranscriptional pages 2-4) | Sheng et al., Cell Reports – https://doi.org/10.1016/j.celrep.2024.114889 (2024); Tian et al., 2016 (2016) |
| Key interaction partners | - UBL-5 (small ubiquitin-like protein)
- LIN-65, MET-2 (chromatin modifiers)
- Functional relationship with ATFS-1 (parallel/coordinate UPRmt regulation) | Biochemical/genetic evidence: DVE-1/UBL-5 complex formation and LIN-65/MET-2 required for nuclear DVE-1 accumulation and UPRmt activation; ATFS-1 acts in a parallel mito-import sensing branch. (haynes2007clppmediatesactivation pages 1-2, tian2016mitochondrialstressinduces pages 9-11, haynes2022mitochondrialdysfunctionaging pages 6-7) | Haynes et al., 2007 (2007); Tian et al., 2016 (2016); Haynes & Hekimi, 2022 (2022) |
| DNA-binding motifs / direct targets | - Binds promoters of UPRmt genes (chromatin association documented)
- No single, well-defined short DNA motif reported in available excerpts | ChIP-style promoter association shown for UPRmt targets; comprehensive motif/consensus not reported in cited excerpts. (tian2016mitochondrialstressinduces pages 9-11, sheng2024amitochondrialunfolded pages 3-5) | Tian et al., 2016 (2016); Sheng et al., Cell Reports (2024) |
| Experimental evidence / methods | - Genome-wide and targeted RNAi screens
- Reporter assays: Phsp-6::GFP, Phsp-60::GFP
- Transgenic DVE-1::GFP reporters, confocal imaging
- Lifespan assays, forward genetics (mutant alleles), RNA-seq reanalysis, tissue-specific RNAi, AID depletion | Core experiments demonstrating roles include large RNAi screens, reporter induction assays, imaging of DVE-1 localization, RNA-seq showing extensive DVE-1-dependent transcriptional changes, and forward genetic alleles affecting homeodomain. (haynes2007clppmediatesactivation pages 1-2, alexander2023thehomeodomaintranscriptional pages 2-4, sheng2024amitochondrialunfolded pages 6-8, sheng2024amitochondrialunfolded pages 8-10) | Haynes et al., 2007 (2007); Alexander et al., Nat Commun – https://doi.org/10.1038/s41467-023-43281-4 (2023); Sheng et al., 2024 (2024) |
| 2023–2024 developments | - Synapse elimination: DVE-1 required cell-autonomously in GABAergic neurons to remove juvenile postsynaptic sites (Alexander et al., 2023)
- UPRmt-independent longevity roles: DVE-1 modulates lifespan in dietary restriction, germline-loss, and other contexts separate from canonical UPRmt (Sheng et al., 2024) | New roles expand DVE-1 function beyond classical mito-stress transcription: neuronal circuit remodeling (developmental synapse pruning) and broad transcriptional control linking to longevity independent of hsp-6 induction. (alexander2023thehomeodomaintranscriptional pages 2-4, sheng2024amitochondrialunfolded pages 8-10) | Alexander et al., Nat Commun – https://doi.org/10.1038/s41467-023-43281-4 (2023); Sheng et al., Cell Reports – https://doi.org/10.1016/j.celrep.2024.114889 (2024) |
| Quantitative highlights | - DVE-1 knockdown alters thousands of genes: ~3,177 genes changed by dve-1RNAi vs ~156 by atfs-1RNAi in reanalysis (numbers from Sheng et al.)
- Synapse removal timing: iAChR clusters removed by ~22 h in WT but persist >40 h in dve-1 hypomorph (Alexander et al.) | Large-scale RNA-seq demonstrates DVE-1's broad transcriptional reach; synapse-removal timing provides a clear developmental phenotype for neuronal function. (sheng2024amitochondrialunfolded pages 10-11, alexander2023thehomeodomaintranscriptional pages 2-4) | Sheng et al., Cell Reports (2024); Alexander et al., Nat Commun (2023) |
| Phenotypes and organismal effects | - Null alleles are embryonic lethal; hypomorphic/homeodomain mutants show synaptic remodeling defects
- dve-1(RNAi) attenuates UPRmt reporter induction and modifies lifespan outcomes variably (can suppress or enhance depending on background) | Essential gene with separable molecular roles: loss affects development and stress signaling; genetic background/context (e.g., isp-1, nuo-6, daf-10, eat-2, glp-1) determines whether dve-1 loss alters lifespan positively or negatively. (haynes2007clppmediatesactivation pages 1-2, sheng2024amitochondrialunfolded pages 6-8, sheng2024amitochondrialunfolded pages 8-10) | Haynes et al., 2007 (2007); Sheng et al., 2024 (2024); Alexander et al., 2023 (2023) |
| Representative references (short) | - Haynes et al., ClpP & UPRmt: https://doi.org/10.1016/j.devcel.2007.07.016 (2007)
- Tian et al., Chromatin & UPRmt: https://doi.org/10.1016/j.cell.2016.04.011 (2016)
- Alexander et al., Synapse elimination: https://doi.org/10.1038/s41467-023-43281-4 (2023)
- Sheng et al., UPRmt-independent longevity: https://doi.org/10.1016/j.celrep.2024.114889 (2024)
- Haynes & Hekimi, Review: https://doi.org/10.1093/genetics/iyac160 (2022) | These provide primary mechanistic, developmental, genomic, and recent functional insights summarized above. (haynes2007clppmediatesactivation pages 1-2, tian2016mitochondrialstressinduces pages 9-11, alexander2023thehomeodomaintranscriptional pages 2-4, sheng2024amitochondrialunfolded pages 8-10, haynes2022mitochondrialdysfunctionaging pages 6-7) | Haynes et al., Dev Cell (2007); Tian et al., Cell (2016); Alexander et al., Nat Commun (2023); Sheng et al., Cell Reports (2024); Haynes & Hekimi, Genetics (2022) |

Table: Concise, evidence-backed summary of C. elegans dve-1 (UniProt Q86MI0) covering identity, domains, functions, pathways (UPRmt), localization, partners, methods, 2023–2024 discoveries, quantitative data, and key citations for follow-up.

Conclusions
DVE-1 (Q86MI0) is the C. elegans homeodomain/SATB-like transcriptional regulator that integrates mitochondrial stress with nuclear gene expression via chromatin reorganization. In canonical UPRmt, DVE-1 forms a complex with UBL-5 and cooperates with chromatin modifiers and ATFS-1 to induce mitochondrial chaperones/proteases; its nuclear accumulation is a hallmark of mitochondrial stress. Recent studies show DVE-1 also directs synapse elimination during neuronal remodeling and modulates longevity across diverse physiological states, often decoupled from canonical UPRmt reporter activation. These findings position DVE-1 as a chromatin-embedded hub that tunes proteostasis, neuronal development, and organismal lifespan in a context-dependent manner (haynes2007clppmediatesactivation pages 1-2, tian2016mitochondrialstressinduces pages 9-11, alexander2023thehomeodomaintranscriptional pages 2-4, sheng2024amitochondrialunfolded pages 8-10, sheng2024amitochondrialunfolded pages 10-11, sheng2024amitochondrialunfolded pages 6-8, haynes2022mitochondrialdysfunctionaging pages 6-7).

References

(haynes2007clppmediatesactivation pages 1-2): Cole M. Haynes, Kseniya Petrova, Cristina Benedetti, Yun Yang, and David Ron. Clpp mediates activation of a mitochondrial unfolded protein response in c. elegans. Developmental cell, 13 4:467-80, Oct 2007. URL: https://doi.org/10.1016/j.devcel.2007.07.016, doi:10.1016/j.devcel.2007.07.016. This article has 690 citations and is from a highest quality peer-reviewed journal.
(tian2016mitochondrialstressinduces pages 9-11): Ye Tian, Gilberto Garcia, Qian Bian, Kristan K. Steffen, Larry Joe, Suzanne Wolff, Barbara J. Meyer, and Andrew Dillin. Mitochondrial stress induces chromatin reorganization to promote longevity and uprmt. Cell, 165:1197-1208, May 2016. URL: https://doi.org/10.1016/j.cell.2016.04.011, doi:10.1016/j.cell.2016.04.011. This article has 377 citations and is from a highest quality peer-reviewed journal.
(alexander2023thehomeodomaintranscriptional pages 2-4): Kellianne D Alexander, Shankar Ramachandran, Kasturi Biswas, Christopher M. Lambert, Julia Russell, Devyn B Oliver, William Armstrong, Monika Rettler, Samuel Liu, M. Doitsidou, Claire Y. Bénard, Amy K. Walker, and Michael M. Francis. The homeodomain transcriptional regulator dve-1 directs a program for synapse elimination during circuit remodeling. Nature Communications, Nov 2023. URL: https://doi.org/10.1038/s41467-023-43281-4, doi:10.1038/s41467-023-43281-4. This article has 4 citations and is from a highest quality peer-reviewed journal.
(sheng2024amitochondrialunfolded pages 8-10): Yi Sheng, Adriana Abreu, Zachary Markovich, Pearl Ebea, Leah Davis, Eric Park, Peike Sheng, Mingyi Xie, Sung Min Han, and Rui Xiao. A mitochondrial unfolded protein response-independent role of dve-1 in longevity regulation. Cell Reports, 43:114889, Nov 2024. URL: https://doi.org/10.1016/j.celrep.2024.114889, doi:10.1016/j.celrep.2024.114889. This article has 2 citations and is from a highest quality peer-reviewed journal.
(sheng2024amitochondrialunfolded pages 10-11): Yi Sheng, Adriana Abreu, Zachary Markovich, Pearl Ebea, Leah Davis, Eric Park, Peike Sheng, Mingyi Xie, Sung Min Han, and Rui Xiao. A mitochondrial unfolded protein response-independent role of dve-1 in longevity regulation. Cell Reports, 43:114889, Nov 2024. URL: https://doi.org/10.1016/j.celrep.2024.114889, doi:10.1016/j.celrep.2024.114889. This article has 2 citations and is from a highest quality peer-reviewed journal.
(sheng2024amitochondrialunfolded pages 6-8): Yi Sheng, Adriana Abreu, Zachary Markovich, Pearl Ebea, Leah Davis, Eric Park, Peike Sheng, Mingyi Xie, Sung Min Han, and Rui Xiao. A mitochondrial unfolded protein response-independent role of dve-1 in longevity regulation. Cell Reports, 43:114889, Nov 2024. URL: https://doi.org/10.1016/j.celrep.2024.114889, doi:10.1016/j.celrep.2024.114889. This article has 2 citations and is from a highest quality peer-reviewed journal.
(haynes2022mitochondrialdysfunctionaging pages 6-7): Cole M Haynes and Siegfried Hekimi. Mitochondrial dysfunction, aging, and the mitochondrial unfolded protein response in caenorhabditis elegans. Genetics, Nov 2022. URL: https://doi.org/10.1093/genetics/iyac160, doi:10.1093/genetics/iyac160. This article has 32 citations and is from a domain leading peer-reviewed journal.
(sheng2024amitochondrialunfolded pages 3-5): Yi Sheng, Adriana Abreu, Zachary Markovich, Pearl Ebea, Leah Davis, Eric Park, Peike Sheng, Mingyi Xie, Sung Min Han, and Rui Xiao. A mitochondrial unfolded protein response-independent role of dve-1 in longevity regulation. Cell Reports, 43:114889, Nov 2024. URL: https://doi.org/10.1016/j.celrep.2024.114889, doi:10.1016/j.celrep.2024.114889. This article has 2 citations and is from a highest quality peer-reviewed journal.

Citations

alexander2023thehomeodomaintranscriptional pages 2-4
haynes2022mitochondrialdysfunctionaging pages 6-7
tian2016mitochondrialstressinduces pages 9-11
sheng2024amitochondrialunfolded pages 10-11
haynes2007clppmediatesactivation pages 1-2
sheng2024amitochondrialunfolded pages 8-10
sheng2024amitochondrialunfolded pages 6-8
sheng2024amitochondrialunfolded pages 3-5
https://doi.org/10.1016/j.devcel.2007.07.016
https://doi.org/10.1016/j.cell.2016.04.011
https://doi.org/10.1093/genetics/iyac160
https://doi.org/10.1016/j.celrep.2024.114889
https://doi.org/10.1038/s41467-023-43281-4
https://doi.org/10.1016/j.devcel.2007.07.016,
https://doi.org/10.1016/j.cell.2016.04.011,
https://doi.org/10.1038/s41467-023-43281-4,
https://doi.org/10.1016/j.celrep.2024.114889,
https://doi.org/10.1093/genetics/iyac160,

📄 View Raw YAML

id: Q86MI0
gene_symbol: dve-1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: DVE-1 is a homeodomain-containing transcription factor orthologous
  to Drosophila defective proventriculus (Dve) and mammalian SATB family
  proteins. It functions as a chromatin-associated regulator essential for the
  mitochondrial unfolded protein response (UPR-mt). DVE-1 forms a complex with
  UBL-5 and interacts with chromatin modifiers including HDA-1 (HDAC1/2
  ortholog), the NuRD complex (via LIN-40), and histone methyltransferase MET-2.
  Upon mitochondrial stress, DVE-1 translocates from cytosol to nucleus where it
  binds promoters of mitochondrial chaperone genes (hsp-6, hsp-60) to enable
  their transcriptional activation. SUMOylation at K327 regulates DVE-1
  subcellular localization, with desumoylation by ULP-4 required for nuclear
  accumulation. Beyond UPR-mt, DVE-1 regulates thousands of genes involved in
  innate immunity, lipid metabolism, and longevity, often independently of the
  canonical ATFS-1 pathway. Recent work reveals additional roles in
  developmental synapse elimination in GABAergic neurons. DVE-1 is essential for
  embryonic development.
existing_annotations:
  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase
        II-specific
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: DVE-1 is a homeodomain-containing transcription factor that
        regulates RNA polymerase II-dependent transcription of UPR-mt target
        genes (hsp-6, hsp-60) and thousands of additional genes. The SATB-like
        domain structure and experimental evidence from reporter assays support
        this annotation.
      action: ACCEPT
      reason: The IBA annotation is well-supported by experimental evidence.
        DVE-1 contains two homeobox DNA-binding domains (UniProt features) and
        functions as a transcription factor that directly regulates gene
        expression. PMID:17925224 demonstrates DVE-1 binds to promoters of
        mitochondrial chaperone genes and is required for their transcriptional
        activation. PMID:35021096 shows DVE-1 binds to the nhr-80 promoter to
        transactivate its expression. The phylogenetic inference from SATB
        family members is consistent with experimental findings.
      supported_by:
        - reference_id: PMID:17925224
          supporting_text: Unfolded protein stress in the mitochondria
            correlates with complex formation between a homeodomain-containing
            transcription factor DVE-1 and the small ubiquitin-like protein
            UBL-5
        - reference_id: PMID:35021096
          supporting_text: The transcription factor DVE-1 binds to the promoter
            of the nuclear hormone receptor nhr-80 to transactivate its
            expression
  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: DVE-1 regulates transcription of numerous genes by RNA polymerase
        II, including UPR-mt target genes and genes involved in lipid
        metabolism, innate immunity, and longevity.
      action: ACCEPT
      reason: This IBA annotation is supported by extensive experimental
        evidence. DVE-1 is required for transcriptional activation of hsp-6 and
        hsp-60 reporters under mitochondrial stress (PMID:17925224). RNA-seq
        analyses show DVE-1 knockdown affects thousands of genes (deep research
        report cites ~3,177 genes changed by dve-1 RNAi). DVE-1 also activates
        nhr-80 transcription linking UPR-mt to lipid metabolism (PMID:35021096).
      supported_by:
        - reference_id: PMID:17925224
          supporting_text: Unfolded protein stress in the mitochondria
            correlates with complex formation between a homeodomain-containing
            transcription factor DVE-1 and the small ubiquitin-like protein
            UBL-5
        - reference_id: PMID:35021096
          supporting_text: Inactivation of DVE-1 or NHR-80 fully abolishes the
            citrate-induced lipid accumulation
  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA
        binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: DVE-1 contains two homeobox DNA-binding domains and binds to
        promoter regions of target genes including mitochondrial chaperone genes
        and nhr-80.
      action: ACCEPT
      reason: The IBA annotation is consistent with DVE-1's domain structure
        (two homeobox domains, SATB-like features) and experimental evidence
        showing DVE-1 binds to promoters of UPR-mt genes (PMID:17925224) and the
        nhr-80 promoter (PMID:35021096). While a specific consensus DNA binding
        motif has not been definitively established, the promoter binding
        activity supports sequence-specific DNA binding.
      supported_by:
        - reference_id: PMID:17925224
          supporting_text: Activation of the UPR(mt) correlates temporally and
            spatially with nuclear redistribution of DVE-1 and with its enhanced
            binding to the promoters of mitochondrial chaperone genes
        - reference_id: PMID:35021096
          supporting_text: The transcription factor DVE-1 binds to the promoter
            of the nuclear hormone receptor nhr-80 to transactivate its
            expression
  - term:
      id: GO:0006338
      label: chromatin remodeling
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: DVE-1 participates in chromatin remodeling as part of the UPR-mt
        response. It associates with the NuRD chromatin remodeling complex and
        cooperates with chromatin modifiers to enable stress-responsive gene
        expression.
      action: ACCEPT
      reason: DVE-1 functions within a chromatin reorganization hub during
        mitochondrial stress. PMID:32789178 shows DVE-1 associates with the NuRD
        complex via LIN-40, mediating chromatin remodeling in response to
        acetyl-CoA levels. PMID:32934238 demonstrates DVE-1 interacts with HDA-1
        to regulate chromatin state for UPR-mt gene expression. The SATB family
        homology further supports genome-organizing functions.
      supported_by:
        - reference_id: PMID:32789178
          supporting_text: NuRD mediates mitochondrial stress-induced longevity
            via chromatin remodeling in response to acetyl-CoA level
        - reference_id: PMID:32934238
          supporting_text: HDA-1 interacts and coordinates with the genome
            organizer DVE-1 to induce the transcription of a broad spectrum of
            UPRmt, innate immune response and metabolic reprogramming genes
  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: DVE-1 contains two homeobox DNA-binding domains and binds DNA at
        promoter regions of target genes.
      action: ACCEPT
      reason: This IEA annotation is correctly inferred from DVE-1's domain
        architecture. The protein contains two homeobox domains (UniProt FT
        DNA_BIND 179-248 and 385-458) which are well-characterized DNA-binding
        domains. Experimental evidence confirms DVE-1 binds to promoters of
        mitochondrial chaperone genes (PMID:17925224) and nhr-80
        (PMID:35021096). The more specific term GO:0000978 is also annotated.
      supported_by:
        - reference_id: PMID:17925224
          supporting_text: Activation of the UPR(mt) correlates temporally and
            spatially with nuclear redistribution of DVE-1 and with its enhanced
            binding to the promoters of mitochondrial chaperone genes
  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: DVE-1 functions as a DNA-binding transcription factor that
        regulates expression of UPR-mt genes and many other targets.
      action: ACCEPT
      reason: This IEA annotation is accurate and supported by experimental
        evidence. DVE-1 contains homeobox DNA-binding domains and directly
        activates transcription of target genes. PMID:35021096 explicitly
        identifies DVE-1 as a transcription factor that transactivates nhr-80
        expression. The more specific term GO:0000981 (RNA polymerase
        II-specific) is also appropriately annotated.
      supported_by:
        - reference_id: PMID:35021096
          supporting_text: The transcription factor DVE-1 binds to the promoter
            of the nuclear hormone receptor nhr-80 to transactivate its
            expression
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: DVE-1 localizes to the nucleus, particularly under mitochondrial
        stress conditions when it translocates from cytosol to nucleus.
      action: ACCEPT
      reason: Nuclear localization of DVE-1 is well-established by multiple
        experimental studies using DVE-1::GFP reporters. PMID:17925224,
        PMID:30642431, PMID:32934238, and PMID:32789178 all demonstrate nuclear
        localization. The IEA inference is correct, though this annotation is
        superseded by IDA evidence from multiple publications.
      supported_by:
        - reference_id: PMID:17925224
          supporting_text: Activation of the UPR(mt) correlates temporally and
            spatially with nuclear redistribution of DVE-1 and with its enhanced
            binding to the promoters of mitochondrial chaperone genes
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: DVE-1 is found in the cytosol under basal conditions and
        translocates to the nucleus upon mitochondrial stress. SUMOylation at
        K327 retains DVE-1 in cytosol.
      action: ACCEPT
      reason: Cytosolic localization is supported by experimental evidence.
        PMID:30642431 demonstrates that SUMOylated DVE-1 localizes to the
        cytosol, and desumoylation by ULP-4 is required for nuclear accumulation
        during mitochondrial stress. UniProt notes that DVE-1 translocates from
        cytosol to nucleus upon mitochondrial stress.
      supported_by:
        - reference_id: PMID:30642431
          supporting_text: Conversely, SUMO-mimetic DVE-1 constitutively
            localized in the cytosol (Figure 3G)
  - term:
      id: GO:0006338
      label: chromatin remodeling
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: DVE-1 participates in chromatin remodeling via interaction with
        NuRD complex and HDA-1.
      action: ACCEPT
      reason: This IEA annotation (from InterPro) is consistent with DVE-1's
        SATB-like domain structure and experimental evidence. DVE-1 associates
        with the NuRD chromatin remodeling complex (PMID:32789178) and
        cooperates with HDA-1 (PMID:32934238) to regulate chromatin state.
        Duplicate with IBA annotation above but both are acceptable given
        different evidence sources.
      supported_by:
        - reference_id: PMID:32789178
          supporting_text: NuRD mediates mitochondrial stress-induced longevity
            via chromatin remodeling in response to acetyl-CoA level
  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: DVE-1 regulates RNA polymerase II-dependent transcription of many
        genes.
      action: ACCEPT
      reason: This IEA annotation is accurate. DVE-1 regulates transcription of
        UPR-mt target genes and thousands of additional genes. This is a
        duplicate of the IBA annotation but from a different evidence source.
        Both are acceptable.
      supported_by:
        - reference_id: PMID:17925224
          supporting_text: Unfolded protein stress in the mitochondria
            correlates with complex formation between a homeodomain-containing
            transcription factor DVE-1 and the small ubiquitin-like protein
            UBL-5
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: DVE-1 positively regulates transcription of UPR-mt target genes
        including hsp-6, hsp-60, and nhr-80.
      action: ACCEPT
      reason: This annotation is well-supported. DVE-1 functions as a
        transcriptional activator for mitochondrial chaperone genes during
        UPR-mt (PMID:17925224) and for nhr-80 in lipid metabolism
        (PMID:35021096). The IDA annotation for GO:0001228 (DNA-binding
        transcription activator activity) provides direct experimental support
        for this role.
      supported_by:
        - reference_id: PMID:35021096
          supporting_text: The transcription factor DVE-1 binds to the promoter
            of the nuclear hormone receptor nhr-80 to transactivate its
            expression
  - term:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase
        II-specific
    evidence_type: IDA
    original_reference_id: PMID:35021096
    review:
      summary: DVE-1 functions as a transcriptional activator, directly binding
        to the nhr-80 promoter and transactivating its expression in response to
        citrate-induced UPR-mt.
      action: ACCEPT
      reason: This IDA annotation from PMID:35021096 is directly supported by
        experimental evidence showing DVE-1 binds to and transactivates the
        nhr-80 promoter. The study demonstrates the DVE-1-NHR-80-lipogenesis
        axis linking mitochondrial stress to lipid metabolism. Inactivation of
        DVE-1 abolishes citrate-induced lipid accumulation.
      supported_by:
        - reference_id: PMID:35021096
          supporting_text: The transcription factor DVE-1 binds to the promoter
            of the nuclear hormone receptor nhr-80 to transactivate its
            expression
  - term:
      id: GO:0045088
      label: regulation of innate immune response
    evidence_type: IMP
    original_reference_id: PMID:32934238
    review:
      summary: DVE-1 is required for UPR-mt-mediated innate immune responses,
        including survival against pathogen challenge.
      action: ACCEPT
      reason: PMID:32934238 demonstrates that dve-1 RNAi suppresses activation
        of immune response genes and reduces survival when animals are
        challenged with pathogens (Pseudomonas, Rhodococcus) under mitochondrial
        stress conditions. DVE-1 cooperates with HDA-1 to induce transcription
        of innate immune response genes.
      supported_by:
        - reference_id: PMID:32934238
          supporting_text: hda-1 or dve-1 RNAi also suppressed the activation of
            the immune response and reduced the survival rate when the animals
            were challenged with another mitochondrial insult, a Rhodococcus
            strain isolated from the natural habitat of C. elegans
  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: IDA
    original_reference_id: PMID:32934238
    review:
      summary: DVE-1 associates with chromatin where it functions as a genome
        organizer coordinating with HDA-1 and the NuRD complex.
      action: ACCEPT
      reason: PMID:32934238 describes DVE-1 as a "genome organizer" that
        coordinates with HDA-1 at chromatin to regulate gene expression.
        PMID:32789178 shows DVE-1 associates with the NuRD complex. DVE-1 binds
        to promoter chromatin of target genes. The SATB family homology further
        supports chromatin association.
      supported_by:
        - reference_id: PMID:32934238
          supporting_text: HDA-1 interacts and coordinates with the genome
            organizer DVE-1 to induce the transcription of a broad spectrum of
            UPRmt, innate immune response and metabolic reprogramming genes
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:32934238
    review:
      summary: DVE-1::GFP accumulates in the nucleus under mitochondrial stress
        conditions.
      action: ACCEPT
      reason: PMID:32934238 uses DVE-1::GFP reporter to demonstrate nuclear
        localization. Multiple other publications (PMID:17925224, PMID:30642431,
        PMID:32789178) confirm nuclear localization of DVE-1 during
        mitochondrial stress using similar approaches.
      supported_by:
        - reference_id: PMID:32934238
          supporting_text: HDA-1 interacts and coordinates with the genome
            organizer DVE-1 to induce the transcription of a broad spectrum of
            UPRmt, innate immune response and metabolic reprogramming genes
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IPI
    original_reference_id: PMID:30642431
    review:
      summary: DVE-1 interacts with the SUMO peptidase ULP-4, which desumoylates
        DVE-1 at K327 to allow nuclear accumulation during UPR-mt.
      action: ACCEPT
      reason: DVE-1 interacts with ULP-4 (PMID:30642431), a SUMO peptidase
        enzyme. ULP-4 is an enzyme and DVE-1 is its substrate, so enzyme binding
        accurately describes this interaction. The interaction is functionally
        important for regulating DVE-1 localization during mitochondrial stress.
      supported_by:
        - reference_id: PMID:30642431
          supporting_text: DVE-1 interacts with ULP-4 and SMO-1 in yeast
            two-hybrid assay
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IPI
    original_reference_id: PMID:32934238
    review:
      summary: DVE-1 interacts with HDA-1 (histone deacetylase), an enzyme that
        modifies chromatin.
      action: ACCEPT
      reason: PMID:32934238 demonstrates that DVE-1 interacts with HDA-1, the C.
        elegans ortholog of mammalian HDAC1/2. HDA-1 is a histone deacetylase
        enzyme. The interaction coordinates chromatin regulation for UPR-mt gene
        expression. "Enzyme binding" accurately describes this interaction.
      supported_by:
        - reference_id: PMID:32934238
          supporting_text: HDA-1 interacts and coordinates with the genome
            organizer DVE-1 to induce the transcription of a broad spectrum of
            UPRmt, innate immune response and metabolic reprogramming genes
  - term:
      id: GO:0034514
      label: mitochondrial unfolded protein response
    evidence_type: IMP
    original_reference_id: PMID:30642431
    review:
      summary: DVE-1 is essential for the mitochondrial unfolded protein
        response. SUMOylation regulates DVE-1 localization during UPR-mt
        activation.
      action: ACCEPT
      reason: PMID:30642431 demonstrates that ULP-4-mediated desumoylation of
        DVE-1 is required for UPR-mt activation. DVE-1 is one of two key
        transcription factors (along with ATFS-1) governing the UPR-mt
        transcriptional program. dve-1 RNAi attenuates hsp-6/hsp-60 reporter
        induction.
      supported_by:
        - reference_id: PMID:30642431
          supporting_text: during mitochondrial stress, ULP-4 deSUMOylates DVE-1
            at K327 residue to allow its nuclear accumulation to initiate UPRmt
  - term:
      id: GO:0044877
      label: protein-containing complex binding
    evidence_type: IDA
    original_reference_id: PMID:32789178
    review:
      summary: DVE-1 associates with the NuRD (Nucleosome Remodeling and
        Deacetylase) complex via interaction with LIN-40.
      action: ACCEPT
      reason: PMID:32789178 demonstrates DVE-1 interacts with LIN-40 and
        associates with the NuRD complex. This interaction mediates chromatin
        remodeling in response to mitochondrial stress and acetyl-CoA levels.
        The annotation accurately reflects DVE-1's binding to this multi-protein
        complex.
      supported_by:
        - reference_id: PMID:32789178
          supporting_text: NuRD mediates mitochondrial stress-induced longevity
            via chromatin remodeling in response to acetyl-CoA level
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32789178
    review:
      summary: DVE-1 interacts with LIN-40, a component of the NuRD complex.
      action: MARK_AS_OVER_ANNOTATED
      reason: While DVE-1 does interact with LIN-40 (PMID:32789178), "protein
        binding" is too generic and uninformative. The more specific annotation
        GO:0044877 "protein-containing complex binding" from the same
        publication better captures this interaction. GO guidelines recommend
        avoiding generic "protein binding" when more specific terms apply.
      supported_by:
        - reference_id: PMID:32789178
          supporting_text: NuRD mediates mitochondrial stress-induced longevity
            via chromatin remodeling in response to acetyl-CoA level
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:30642431
    review:
      summary: DVE-1 localizes to nucleus upon mitochondrial stress after
        desumoylation by ULP-4.
      action: ACCEPT
      reason: PMID:30642431 uses DVE-1::GFP imaging to demonstrate nuclear
        localization. The study shows that desumoylation at K327 is required for
        nuclear accumulation during mitochondrial stress. DVE-1 K327R
        (non-SUMOylatable) constitutively localizes to the nucleus.
      supported_by:
        - reference_id: PMID:30642431
          supporting_text: DVE-1 K327R constitutively localized in the nucleus
            of C. elegans, even if ulp-4 was knocked down by RNAi (Figure 3F)
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:32789178
    review:
      summary: DVE-1::GFP shows nuclear localization in response to
        mitochondrial stress.
      action: ACCEPT
      reason: PMID:32789178 demonstrates nuclear accumulation of DVE-1::GFP
        under mitochondrial stress conditions using fluorescence microscopy.
        This is consistent with other publications. Duplicate annotations with
        different references are acceptable.
      supported_by:
        - reference_id: PMID:32789178
          supporting_text: NuRD mediates mitochondrial stress-induced longevity
            via chromatin remodeling in response to acetyl-CoA level
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: PMID:30642431
    review:
      summary: SUMOylated DVE-1 localizes to the cytosol. Desumoylation by ULP-4
        allows nuclear translocation.
      action: ACCEPT
      reason: PMID:30642431 directly demonstrates that SUMOylation at K327
        retains DVE-1 in the cytosol. A SUMO-mimetic DVE-1 fusion constitutively
        localizes to the cytosol. This provides direct evidence for cytosolic
        localization under specific conditions.
      supported_by:
        - reference_id: PMID:30642431
          supporting_text: Conversely, SUMO-mimetic DVE-1 constitutively
            localized in the cytosol (Figure 3G)
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: PMID:32789178
    review:
      summary: DVE-1 can be found in the cytosol, consistent with its
        stress-induced translocation from cytosol to nucleus.
      action: ACCEPT
      reason: PMID:32789178 studies DVE-1::GFP localization dynamics. The
        cytosolic pool of DVE-1 translocates to nucleus upon mitochondrial
        stress. UniProt annotates cytosol based on this evidence.
      supported_by:
        - reference_id: PMID:32789178
          supporting_text: NuRD mediates mitochondrial stress-induced longevity
            via chromatin remodeling in response to acetyl-CoA level
  - term:
      id: GO:0034514
      label: mitochondrial unfolded protein response
    evidence_type: IMP
    original_reference_id: PMID:30057120
    review:
      summary: DVE-1 functions in cell-non-autonomous UPR-mt signaling mediated
        by Wnt signaling.
      action: ACCEPT
      reason: PMID:30057120 examines cell-non-autonomous UPR-mt signaling via
        Wnt pathway. DVE-1 is a known component of the UPR-mt transcriptional
        program activated downstream of this signaling. The publication expands
        understanding of how UPR-mt is coordinated across tissues.
      supported_by:
        - reference_id: PMID:30057120
          supporting_text: The mitochondrial unfolded protein response (UPRmt)
            can be triggered in a cell-non-autonomous fashion
  - term:
      id: GO:0034514
      label: mitochondrial unfolded protein response
    evidence_type: IMP
    original_reference_id: PMID:17925224
    review:
      summary: DVE-1 was identified as a key regulator of UPR-mt in the
        foundational genome-wide RNAi screen. Required for activation of
        mitochondrial chaperone gene expression.
      action: ACCEPT
      reason: PMID:17925224 is the seminal publication identifying DVE-1's role
        in UPR-mt. A genome-wide RNAi screen identified dve-1 as required for
        UPR-mt signaling. DVE-1 forms a complex with UBL-5, redistributes to
        nucleus, and binds to promoters of mitochondrial chaperone genes under
        stress.
      supported_by:
        - reference_id: PMID:17925224
          supporting_text: Unfolded protein stress in the mitochondria
            correlates with complex formation between a homeodomain-containing
            transcription factor DVE-1 and the small ubiquitin-like protein
            UBL-5, both of which are encoded by genes required for signaling the
            UPR(mt)
  - term:
      id: GO:0005667
      label: transcription regulator complex
    evidence_type: IPI
    original_reference_id: PMID:17925224
    review:
      summary: DVE-1 forms a complex with UBL-5 to regulate UPR-mt gene
        transcription. This complex forms specifically under mitochondrial
        stress conditions.
      action: ACCEPT
      reason: PMID:17925224 demonstrates that DVE-1 and UBL-5 form a complex in
        a mitochondrial stress-dependent manner. This DVE-1/UBL-5 complex is
        required for transcriptional regulation of UPR-mt target genes. UniProt
        confirms the interaction.
      supported_by:
        - reference_id: PMID:17925224
          supporting_text: Unfolded protein stress in the mitochondria
            correlates with complex formation between a homeodomain-containing
            transcription factor DVE-1 and the small ubiquitin-like protein
            UBL-5
  - term:
      id: GO:0051087
      label: protein-folding chaperone binding
    evidence_type: IPI
    original_reference_id: PMID:17925224
    review:
      summary: DVE-1 interacts with UBL-5, which has chaperone-like properties
        and is part of the UPR-mt regulatory complex.
      action: UNDECIDED
      reason: While DVE-1 interacts with UBL-5, it is unclear whether UBL-5
        functions as a protein-folding chaperone. UBL-5 is a small
        ubiquitin-like protein that forms a complex with DVE-1 during
        mitochondrial stress, but its classification as a chaperone is not
        well-established. This annotation may be based on interpretation of
        UBL-5 function that requires further validation.
      supported_by:
        - reference_id: PMID:17925224
          supporting_text: Unfolded protein stress in the mitochondria
            correlates with complex formation between a homeodomain-containing
            transcription factor DVE-1 and the small ubiquitin-like protein
            UBL-5
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:17925224
    review:
      summary: DVE-1 redistributes to the nucleus under mitochondrial stress, as
        shown by the foundational UPR-mt study.
      action: ACCEPT
      reason: PMID:17925224 demonstrates nuclear redistribution of DVE-1
        correlates with UPR-mt activation. This is the original publication
        establishing DVE-1 nuclear localization during mitochondrial stress.
      supported_by:
        - reference_id: PMID:17925224
          supporting_text: Activation of the UPR(mt) correlates temporally and
            spatially with nuclear redistribution of DVE-1 and with its enhanced
            binding to the promoters of mitochondrial chaperone genes
  - term:
      id: GO:0009792
      label: embryo development ending in birth or egg hatching
    evidence_type: IMP
    original_reference_id: PMID:17925224
    review:
      summary: DVE-1 is essential for embryonic development. Null alleles are
        embryonic lethal.
      action: KEEP_AS_NON_CORE
      reason: PMID:17925224 and UniProt note that dve-1 is required for
        embryonic development (null alleles are lethal). However, this is likely
        a consequence of DVE-1's essential role in transcriptional regulation
        and chromatin organization rather than a specific developmental
        function. The core function is as a UPR-mt transcriptional regulator and
        chromatin organizer.
      supported_by:
        - reference_id: file:worm/dve-1/dve-1-deep-research-falcon.md
          supporting_text: DVE-1 is required for embryonic development
        - reference_id: PMID:17925224
          supporting_text: ClpP mediates activation of a mitochondrial unfolded
            protein response in C.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings:
      - statement: DVE-1 contains homeobox domains and SATB-like features that
          predict DNA binding and chromatin organization functions.
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings:
      - statement: DVE-1 is orthologous to Drosophila Dve and mammalian
          SATB1/SATB2, supporting transcription factor and chromatin
          organization functions.
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular
      Location vocabulary mapping
    findings:
      - statement: DVE-1 localizes to both cytosol and nucleus depending on
          stress state.
  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference, based on
      inter-ontology links
    findings:
      - statement: Positive regulation of transcription inferred from activator
          activity annotations.
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings:
      - statement: Transcription factor activity correctly predicted from domain
          structure.
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings:
      - statement: DNA binding and nuclear localization correctly inferred from
          homeobox domains.
  - id: PMID:17925224
    title: ClpP mediates activation of a mitochondrial unfolded protein response
      in C. elegans.
    findings:
      - statement: Identified DVE-1 as essential for UPR-mt signaling via
          genome-wide RNAi screen.
        supporting_text: Unfolded protein stress in the mitochondria correlates
          with complex formation between a homeodomain-containing transcription
          factor DVE-1 and the small ubiquitin-like protein UBL-5, both of which
          are encoded by genes required for signaling the UPR(mt)
      - statement: DVE-1 forms stress-dependent complex with UBL-5.
        supporting_text: Unfolded protein stress in the mitochondria correlates
          with complex formation between a homeodomain-containing transcription
          factor DVE-1 and the small ubiquitin-like protein UBL-5
      - statement: DVE-1 redistributes to nucleus and binds promoters of
          mitochondrial chaperone genes under stress.
        supporting_text: Activation of the UPR(mt) correlates temporally and
          spatially with nuclear redistribution of DVE-1 and with its enhanced
          binding to the promoters of mitochondrial chaperone genes
  - id: PMID:30057120
    title: The Mitochondrial Unfolded Protein Response Is Mediated
      Cell-Non-autonomously by Retromer-Dependent Wnt Signaling.
    findings:
      - statement: UPR-mt can be triggered cell-non-autonomously via Wnt
          signaling from neurons to peripheral tissues.
      - statement: DVE-1 functions in downstream transcriptional response to
          these signals.
  - id: PMID:30642431
    title: SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated innate
      immunity and lifespan extension.
    findings:
      - statement: ULP-4 desumoylates DVE-1 at K327 to enable nuclear
          accumulation during UPR-mt.
        supporting_text: during mitochondrial stress, ULP-4 deSUMOylates DVE-1
          at K327 residue to allow its nuclear accumulation to initiate UPRmt
      - statement: SUMOylated DVE-1 is retained in cytosol.
        supporting_text: Conversely, SUMO-mimetic DVE-1 constitutively localized
          in the cytosol (Figure 3G)
      - statement: DVE-1 interacts with ULP-4 and SMO-1 (SUMO).
        supporting_text: DVE-1 interacts with ULP-4 and SMO-1 in yeast
          two-hybrid assay
  - id: PMID:32789178
    title: NuRD mediates mitochondrial stress-induced longevity via chromatin
      remodeling in response to acetyl-CoA level.
    findings:
      - statement: DVE-1 associates with NuRD complex via LIN-40.
        supporting_text: NuRD mediates mitochondrial stress-induced longevity
          via chromatin remodeling in response to acetyl-CoA level
      - statement: Acetyl-CoA levels regulate chromatin remodeling and
          NuRD/DVE-1 nuclear accumulation.
        supporting_text: NuRD mediates mitochondrial stress-induced longevity
          via chromatin remodeling in response to acetyl-CoA level
  - id: PMID:32934238
    title: Histone deacetylase HDA-1 modulates mitochondrial stress response and
      longevity.
    findings:
      - statement: HDA-1 interacts and coordinates with DVE-1 genome organizer.
        supporting_text: HDA-1 interacts and coordinates with the genome
          organizer DVE-1 to induce the transcription of a broad spectrum of
          UPRmt, innate immune response and metabolic reprogramming genes
      - statement: Together they induce transcription of UPR-mt, innate immune,
          and metabolic genes.
        supporting_text: HDA-1 interacts and coordinates with the genome
          organizer DVE-1 to induce the transcription of a broad spectrum of
          UPRmt, innate immune response and metabolic reprogramming genes
      - statement: dve-1 RNAi suppresses immune response and survival against
          pathogens.
        supporting_text: hda-1 or dve-1 RNAi also suppressed the activation of
          the immune response and reduced the survival rate when the animals
          were challenged with another mitochondrial insult, a Rhodococcus
          strain isolated from the natural habitat of C. elegans
  - id: PMID:35021096
    title: NHR-80 senses the mitochondrial UPR to rewire citrate metabolism for
      lipid accumulation in Caenorhabditis elegans.
    findings:
      - statement: DVE-1 binds to nhr-80 promoter and transactivates its
          expression.
        supporting_text: The transcription factor DVE-1 binds to the promoter of
          the nuclear hormone receptor nhr-80 to transactivate its expression
      - statement: DVE-1-NHR-80 axis links UPR-mt to lipid metabolism.
        supporting_text: our work uncovers a DVE-1-NHR-80-lipogenesis axis
          linking the transmission of the mitochondrial stress signal to lipid
          metabolism
      - statement: Inactivation of DVE-1 abolishes citrate-induced lipid
          accumulation.
        supporting_text: Inactivation of DVE-1 or NHR-80 fully abolishes the
          citrate-induced lipid accumulation
  - id: file:worm/dve-1/dve-1-deep-research-falcon.md
    title: Deep research on DVE-1 function
    findings:
      - statement: DVE-1 regulates thousands of genes including those involved
          in lipid metabolism, innate immunity, and longevity.
      - statement: DVE-1 functions as a chromatin organizer similar to mammalian
          SATB family proteins.
      - statement: DVE-1 is required for embryonic development.
core_functions:
  - description: DVE-1 is one of two key transcription factors (with ATFS-1)
      governing the UPR-mt transcriptional program. Identified in foundational
      genome-wide RNAi screen (PMID:17925224). Forms complex with UBL-5 under
      stress. Required for induction of mitochondrial chaperone genes hsp-6 and
      hsp-60. Nuclear localization regulated by SUMOylation/desumoylation
      (PMID:30642431). Coordinates with chromatin modifiers HDA-1
      (PMID:32934238) and NuRD complex (PMID:32789178).
    molecular_function:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase
        II-specific
    directly_involved_in:
      - id: GO:0034514
        label: mitochondrial unfolded protein response
    locations:
      - id: GO:0005634
        label: nucleus
  - description: DVE-1 functions as a chromatin-associated genome organizer.
      Associates with NuRD complex via LIN-40 (PMID:32789178). Coordinates with
      HDA-1 histone deacetylase (PMID:32934238). SATB family homology supports
      roles in higher-order chromatin organization. Chromatin reorganization is
      required for UPR-mt gene accessibility and longevity phenotypes.
    molecular_function:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase
        II-specific
    directly_involved_in:
      - id: GO:0006338
        label: chromatin remodeling
    locations:
      - id: GO:0000785
        label: chromatin
proposed_new_terms:
  - proposed_name: regulation of mitochondrial unfolded protein response
    proposed_definition: Any process that modulates the frequency, rate or
      extent of the mitochondrial unfolded protein response, the series of
      molecular signals generated as a consequence of the presence of unfolded
      proteins in the mitochondrial matrix.
    justification: GO:0034514 (mitochondrial unfolded protein response) exists,
      but a regulatory term would better capture DVE-1's role as a
      transcriptional regulator rather than the response itself. Terms like
      GO:0036499 (regulation of IRE1-mediated UPR) exist for ER-UPR but not for
      UPR-mt.
    proposed_parent:
      id: GO:0034514
      label: mitochondrial unfolded protein response
suggested_questions:
  - question: Does DVE-1 have direct repressor activity for certain gene sets,
      or is it primarily an activator?
  - question: What is the DNA binding motif/consensus sequence for DVE-1 target
      sites?
  - question: How do the two homeobox domains cooperate in DNA binding and
      target selection?
  - question: What determines the context-dependent switch between DVE-1
      activator and repressor functions?
suggested_experiments:
  - description: ChIP-seq for DVE-1 to comprehensively map genomic binding sites
      and identify consensus motif.
    hypothesis: DVE-1 binds to a specific DNA motif at promoters of UPR-mt
      target genes.
  - description: Structure-function analysis of individual homeobox domains to
      determine their contributions.
    hypothesis: The two homeobox domains have distinct or cooperative roles in
      DNA binding.
  - description: Time-resolved proteomics of DVE-1 complexes under different
      stress conditions.
    hypothesis: DVE-1 forms distinct protein complexes under different
      physiological conditions.
  - description: Single-cell analysis of DVE-1 activity across tissues during
      UPR-mt.
    hypothesis: DVE-1 activation varies across cell types during systemic
      mitochondrial stress.
tags:
  - caeel-upr-stress

Gene Description

Proposed New Ontology Terms

regulation of mitochondrial unfolded protein response

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

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Deep Research

Falcon

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