DELE1 (DAP3-binding cell death enhancer 1) is a mitochondrially targeted TPR-repeat protein that relays mitochondrial stress to the cytosolic integrated stress response. At steady state DELE1 is imported into mitochondria, associates with the inner membrane, and is rapidly degraded by the matrix protease LONP1. Mitochondrial stress such as depolarization activates the inner-membrane protease OMA1, which cleaves DELE1 into a C-terminal short form (DELE1-CTD) that is released to the cytosol, oligomerizes, binds the eIF2alpha kinase HRI (EIF2AK1) and activates it. Under iron deficiency, import of full-length DELE1 is arrested and the protein is stabilized on the mitochondrial surface, where it likewise activates HRI. The resulting eIF2alpha phosphorylation attenuates translation and induces ATF4 and other ISR targets, and HRI-dependent phospho-eIF2 at mitochondria promotes PINK1/PRKN-independent mitophagy. An early study also linked DELE1 to death-receptor-induced apoptosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:20563667 Identification of DELE, a novel DAP3-binding protein which i... | REMOVE | Summary: Yeast two-hybrid/co-IP interaction with DAP3, the basis of the original DELE name. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe DELE1 activity. The informative DELE1 interaction (HRI activation) is captured by GO:0043539. Supporting Evidence: PMID:20563667 In this report, we show that DELE actually binds to DAP3 in mammalian cells. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Proteome-scale Y2H interaction (HI-II-14) with CRX. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe DELE1 activity. The informative DELE1 interaction (HRI activation) is captured by GO:0043539. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput Y2H interaction from a neurodegenerative-disease interactome screen. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe DELE1 activity. The informative DELE1 interaction (HRI activation) is captured by GO:0043539. Partners in this screen (e.g. HTT) have no established link to DELE1 function. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput Y2H interaction from a neurodegenerative-disease interactome screen. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe DELE1 activity. The informative DELE1 interaction (HRI activation) is captured by GO:0043539. Partners in this screen (e.g. HTT) have no established link to DELE1 function. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput Y2H interaction from a neurodegenerative-disease interactome screen. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe DELE1 activity. The informative DELE1 interaction (HRI activation) is captured by GO:0043539. Partners in this screen (e.g. HTT) have no established link to DELE1 function. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput Y2H interaction from a neurodegenerative-disease interactome screen. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe DELE1 activity. The informative DELE1 interaction (HRI activation) is captured by GO:0043539. Partners in this screen (e.g. HTT) have no established link to DELE1 function. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput Y2H interaction from a neurodegenerative-disease interactome screen. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe DELE1 activity. The informative DELE1 interaction (HRI activation) is captured by GO:0043539. Partners in this screen (e.g. HTT) have no established link to DELE1 function. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput Y2H interaction from a neurodegenerative-disease interactome screen. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe DELE1 activity. The informative DELE1 interaction (HRI activation) is captured by GO:0043539. Partners in this screen (e.g. HTT) have no established link to DELE1 function. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput Y2H interaction from a neurodegenerative-disease interactome screen. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe DELE1 activity. The informative DELE1 interaction (HRI activation) is captured by GO:0043539. Partners in this screen (e.g. HTT) have no established link to DELE1 function. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput Y2H interaction from a neurodegenerative-disease interactome screen. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe DELE1 activity. The informative DELE1 interaction (HRI activation) is captured by GO:0043539. Partners in this screen (e.g. HTT) have no established link to DELE1 function. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins |
| GO:0005739 mitochondrion | EXP PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | ACCEPT | Summary: Full-length DELE1 is a mitochondrial protein targeted by an N-terminal MTS. Reason: Correct; DELE1 is imported into mitochondria and cleaved by OMA1 under stress. Supporting Evidence: PMID:32132706 Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. |
| GO:0005739 mitochondrion | EXP PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: DELE1 associates with the inner mitochondrial membrane before OMA1 cleavage. Reason: Correct. Supporting Evidence: PMID:32132707 DELE1, a little-characterized protein that we found was associated with the inner mitochondrial membrane. |
| GO:0005739 mitochondrion | EXP PMID:37327776 A mitochondrial iron-responsive pathway regulated by DELE1. | ACCEPT | Summary: DELE1 is imported into mitochondria and degraded by LONP1 at steady state. Reason: Correct. Supporting Evidence: PMID:37327776 Under steady-state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 soon after mitochondrial import. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-confidence mitochondrial proteome (MitoCoP) includes DELE1. Reason: Consistent with low-throughput data. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for mitochondrion in the DELE1 family node. Reason: Correct; human DELE1 is itself the experimental source, as expected for a node with a single characterized member. Supporting Evidence: PMID:32132707 DELE1, a little-characterized protein that we found was associated with the inner mitochondrial membrane. |
| GO:0005739 mitochondrion | IDA PMID:10942595 A visual intracellular classification strategy for uncharact... | ACCEPT | Summary: GFP-fusion localization screen (PROLOC) identified mitochondrial localization. Reason: Consistent with later work. Supporting Evidence: PMID:10942595 This pilot project has identified novel proteins associated with the nucleolus, mitochondria |
| GO:0005739 mitochondrion | IDA PMID:20563667 Identification of DELE, a novel DAP3-binding protein which i... | ACCEPT | Summary: Mitochondrial localization reported in the DELE/DAP3 study. Reason: Correct; UniProt cites this paper for mitochondrion. Supporting Evidence: file:human/DELE1/DELE1-uniprot.txt Mitochondrion {ECO:0000269|PubMed:20563667, |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping. Reason: Correct. Supporting Evidence: file:human/DELE1/DELE1-uniprot.txt Mitochondrion outer membrane {ECO:0000269|PubMed:37327776}. Mitochondrion inner membrane {ECO:0000269|PubMed:32132707}. |
| GO:0005741 mitochondrial outer membrane | IDA PMID:37327776 A mitochondrial iron-responsive pathway regulated by DELE1. | ACCEPT | Summary: Under iron deficiency, import-arrested full-length DELE1 is stabilized on the mitochondrial surface where it activates HRI. Reason: Correct; is_active_in is appropriate for the iron-deficiency branch. Supporting Evidence: PMID:37327776 Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping to mitochondrial outer membrane. Reason: Correct. Supporting Evidence: file:human/DELE1/DELE1-uniprot.txt Mitochondrion outer membrane {ECO:0000269|PubMed:37327776}. Mitochondrion inner membrane {ECO:0000269|PubMed:32132707}. |
| GO:0005743 mitochondrial inner membrane | EXP PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: DELE1 associated with the inner mitochondrial membrane. Reason: Correct. Supporting Evidence: PMID:32132707 DELE1, a little-characterized protein that we found was associated with the inner mitochondrial membrane. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping to mitochondrial inner membrane. Reason: Correct. Supporting Evidence: file:human/DELE1/DELE1-uniprot.txt Mitochondrion outer membrane {ECO:0000269|PubMed:37327776}. Mitochondrion inner membrane {ECO:0000269|PubMed:32132707}. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9840401 | ACCEPT | Summary: Reactome: DELE1 is imported/anchored at the inner membrane before release. Reason: Correct. Supporting Evidence: Reactome:R-HSA-9840401 In unstressed mitochondria, DELE1 is completely imported into the matrix and degraded by LONP1 |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9840408 | ACCEPT | Summary: Reactome: OMA1 cleaves inner-membrane-anchored DELE1. Reason: Correct. Supporting Evidence: Reactome:R-HSA-9840408 Whereas the N-terminal region of uncleaved DELE1 is anchored in the mitochondrial inner membrane |
| GO:0005829 cytosol | IDA PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | ACCEPT | Summary: Cleaved DELE1 short form accumulates in the cytosol where it activates HRI. Reason: Correct site of the kinase-activator function. Supporting Evidence: PMID:32132706 Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. |
| GO:0005829 cytosol | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: Cleaved DELE1 accumulates in the cytosol and interacts with HRI. Reason: Correct. Supporting Evidence: PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (short form) to cytosol. Reason: Correct. Supporting Evidence: file:human/DELE1/DELE1-uniprot.txt Cytoplasm, cytosol {ECO:0000269|PubMed:32132706, ECO:0000269|PubMed:32132707}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9840401 | ACCEPT | Summary: Reactome: DELE1(143-515) is released into the cytosol. Reason: Correct. Supporting Evidence: Reactome:R-HSA-9840401 In unstressed mitochondria, DELE1 is completely imported into the matrix and degraded by LONP1 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9840429 | ACCEPT | Summary: Reactome: DELE1(143-515) binds HRI in the cytosol. Reason: Correct. Supporting Evidence: Reactome:R-HSA-9840429 The C-terminal fragment of cleaved DELE1 interacts with EIF2AK1 (HRI) in the cytosol |
| GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors | IDA PMID:20563667 Identification of DELE, a novel DAP3-binding protein which i... | KEEP AS NON CORE | Summary: DELE knockdown reduced caspase activation and apoptosis induced by TNF-alpha, anti-Fas or TRAIL in HeLa cells. Reason: Single early study (abstract only in cache) predating the discovery of the OMA1-DELE1-HRI pathway; defer to curator, but this is peripheral to the established DELE1 function. Supporting Evidence: PMID:20563667 knockdown of DELE expression rescued the HeLa cells from apoptosis induction by these stimuli. |
| GO:0033554 cellular response to stress | IDA PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | ACCEPT | Summary: DELE1 relays mitochondrial stress to the cytosol to induce the ISR. Reason: Correct but general; the specific process is captured by HRI-mediated signaling (GO:0140468). Supporting Evidence: PMID:32132706 Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. |
| GO:0033554 cellular response to stress | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: DELE1 is required for mitochondrial-stress-induced ATF4 induction. Reason: Correct but general; see GO:0140468. Supporting Evidence: PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:0033554 cellular response to stress | IDA PMID:38340717 The HRI branch of the integrated stress response selectively... | ACCEPT | Summary: DELE1 is required for HRI-dependent responses to mitochondrial damage/iron chelation. Reason: Correct but general. Supporting Evidence: PMID:38340717 Knockdown of either DELE1 or HRI blocked this upregulation of ATF4 |
| GO:0043539 protein serine/threonine kinase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA: protein serine/threonine kinase activator activity. Reason: Correct; human DELE1 is the experimental source for this node. Supporting Evidence: PMID:32132706 Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. |
| GO:0043539 protein serine/threonine kinase activator activity | IDA PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | ACCEPT | Summary: Cleaved DELE1 binds and activates HRI. Reason: Core molecular function. Supporting Evidence: PMID:32132706 Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. |
| GO:0043539 protein serine/threonine kinase activator activity | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: Cytosolic DELE1 activates the eIF2alpha kinase activity of HRI. Reason: Core molecular function. Supporting Evidence: PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:0043539 protein serine/threonine kinase activator activity | IDA PMID:37327776 A mitochondrial iron-responsive pathway regulated by DELE1. | ACCEPT | Summary: Full-length DELE1 stabilized on the mitochondrial surface activates HRI under iron deficiency. Reason: Core molecular function. Supporting Evidence: PMID:37327776 Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). |
| GO:0043539 protein serine/threonine kinase activator activity | IDA PMID:38340717 The HRI branch of the integrated stress response selectively... | ACCEPT | Summary: DELE1 is required for HRI activation in the mitophagy pathway. Reason: Core molecular function (supporting evidence). Supporting Evidence: PMID:38340717 Knockdown of either DELE1 or HRI blocked this upregulation of ATF4 |
| GO:0140468 HRI-mediated signaling | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA: HRI-mediated signaling. Reason: Correct and core. Supporting Evidence: PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:0140468 HRI-mediated signaling | IDA PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | ACCEPT | Summary: OMA1-DELE1-HRI pathway identified by haploid genetic screening. Reason: Core process. Supporting Evidence: PMID:32132706 Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. |
| GO:0140468 HRI-mediated signaling | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: CRISPRi screen identified DELE1 upstream of HRI. Reason: Core process. Supporting Evidence: PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:0140468 HRI-mediated signaling | IDA PMID:37327776 A mitochondrial iron-responsive pathway regulated by DELE1. | ACCEPT | Summary: DELE1-HRI pathway in iron deficiency. Reason: Core process. Supporting Evidence: PMID:37327776 Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). |
| GO:0140468 HRI-mediated signaling | IDA PMID:38340717 The HRI branch of the integrated stress response selectively... | ACCEPT | Summary: DELE1-HRI branch triggers mitophagy. Reason: Core process. Supporting Evidence: PMID:38340717 Knockdown of either DELE1 or HRI blocked this upregulation of ATF4 |
| GO:1901526 positive regulation of mitophagy | IDA PMID:38340717 The HRI branch of the integrated stress response selectively... | KEEP AS NON CORE | Summary: DELE1 knockdown suppressed iron-chelation-induced (DFP) mitophagy, as did HRI and OMA1 knockdown. Reason: Supported; DELE1 acts upstream via HRI and phospho-eIF2alpha, so this is a downstream regulatory outcome rather than the core activity. Supporting Evidence: PMID:38340717 Knockdown of DELE1, OMA1 and HRI suppressed DFP-induced mitophagy, whereas knockdown of ATF4 did not |
| GO:1990641 response to iron ion starvation | IDA PMID:37327776 A mitochondrial iron-responsive pathway regulated by DELE1. | ACCEPT | Summary: DELE1 is required for iron-deficiency-induced HRI activation and protects erythroid cells under iron limitation. Reason: Supported; DELE1 import arrest is the iron-sensing step. Supporting Evidence: PMID:37327776 Here, we show that iron-deficiency-induced HRI activation requires the mitochondrial protein DELE1. PMID:37327776 Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). |
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Download this section (compressed HTML)Q: Does DELE1 respond to accumulation of misfolded matrix proteins per se (a UPRmt-type trigger), or only to import defects and membrane depolarization that activate OMA1?
Q: Is DELE1-CTD oligomerization required in vivo for HRI activation, and how does the oligomer engage the HRI kinase domain?
Experiment: Express misfolding-prone matrix proteins (e.g. deltaOTC) or inhibit LONP1/CLPP in DELE1 knockout versus wild-type cells and measure DELE1 cleavage, HRI autophosphorylation and ATF4 induction.
Hypothesis: Matrix protein misfolding without depolarization is sufficient to activate the DELE1-HRI pathway.
Type: genetic perturbation / signaling readout
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