spg-7

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005745 m-AAA complex	IBA GO_REF:0000033	ACCEPT	Summary: SPG-7 is a well-established component of the m-AAA protease complex based on phylogenetic analysis (IBA from PAINT) and conserved domain architecture with mammalian AFG3L2. UniProt explicitly notes SPG-7 is an ortholog of human AFG3L2 and yeast AFG3, both core m-AAA complex subunits. Deep research confirms conserved m-AAA domain architecture (file:worm/spg-7/spg-7-deep-research-falcon.md). Reason: The IBA annotation is well-supported by phylogenetic conservation and domain analysis. SPG-7 contains characteristic m-AAA protease domains: AAA+ ATPase (IPR003593) and peptidase M41 (IPR000642). This is a core localization for the protein. Supporting Evidence: UniProt:Q9N3T5 Acts as a component of the m-AAA protease complex which is an ATP-dependent metalloprotease mediating degradation of non-assembled mitochondrial inner membrane proteins file:worm/spg-7/spg-7-deep-research-falcon.md spg-7 is inferred to encode an ATP-dependent, zinc metalloprotease that assembles into the m-AAA complex on the matrix side of the inner mitochondrial membrane
GO:0004222 metalloendopeptidase activity	IBA GO_REF:0000033	ACCEPT	Summary: SPG-7 contains a conserved M41 peptidase domain with the HExxH zinc-binding motif characteristic of metalloendopeptidases. The IBA annotation from PAINT is phylogenetically well-supported across m-AAA protease family members. Reason: Core molecular function of SPG-7 is metalloendopeptidase activity. The protein has conserved zinc-binding sites and an active site based on UniProt annotations. This activity is essential for its role in mitochondrial protein processing. Supporting Evidence: UniProt:Q9N3T5 Binds 1 zinc ion per subunit
GO:0034982 mitochondrial protein processing	IBA GO_REF:0000033	ACCEPT	Summary: Mitochondrial protein processing is a core function of m-AAA proteases across eukaryotes. This IBA annotation is well-supported by phylogenetic conservation and is consistent with experimental evidence in C. elegans (PMID:22700657, PMID:25274306, PMID:25773600). Reason: Core biological process for SPG-7. The m-AAA protease processes imported mitochondrial proteins and degrades misfolded proteins. This is directly supported by C. elegans experimental data showing spg-7 RNAi affects mitochondrial function and activates compensatory stress responses. Supporting Evidence: UniProt:Q9N3T5 Acts as a component of the m-AAA protease complex which is an ATP-dependent metalloprotease mediating degradation of non-assembled mitochondrial inner membrane proteins
GO:0000166 nucleotide binding	IEA GO_REF:0000043	MODIFY	Summary: SPG-7 contains an AAA+ ATPase domain with Walker A and Walker B motifs. The IEA annotation from UniProt keyword mapping is correct but overly general. Reason: While accurate, this term is too general. SPG-7 specifically binds and hydrolyzes ATP as part of its ATPase activity. The more specific term GO:0005524 (ATP binding) is already annotated and better captures the function. Proposed replacements: ATP binding
GO:0004176 ATP-dependent peptidase activity	IEA GO_REF:0000002	ACCEPT	Summary: SPG-7 functions as an ATP-dependent peptidase. The AAA+ ATPase domain powers substrate unfolding and translocation into the proteolytic chamber, where the M41 peptidase domain degrades substrates. This is a defining feature of m-AAA proteases. Reason: This term accurately describes SPG-7's integrated molecular function combining ATPase and peptidase activities. The InterPro-based IEA annotation is well-supported by domain architecture. Supporting Evidence: UniProt:Q9N3T5 In the N-terminal section; belongs to the AAA ATPase family
GO:0004222 metalloendopeptidase activity	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate of the IBA annotation for metalloendopeptidase activity. The IEA from InterPro mapping is consistent with the IBA phylogenetic annotation. Reason: Both the IEA (InterPro) and IBA (PAINT) annotations support this core molecular function. Keeping both evidence types is appropriate as they represent independent lines of evidence. Supporting Evidence: UniProt:Q9N3T5 In the C-terminal section; belongs to the peptidase M41 family
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: SPG-7 has a well-characterized ATP-binding site in its AAA+ ATPase domain. ATP binding is essential for m-AAA protease function. Reason: Core molecular function for SPG-7. The AAA+ ATPase domain requires ATP binding for substrate engagement, unfolding, and translocation. Well-supported by domain analysis. Supporting Evidence: UniProt:Q9N3T5 In the N-terminal section; belongs to the AAA ATPase family
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	ACCEPT	Summary: SPG-7 is a mitochondrial inner membrane protein with two transmembrane helices. The protein is anchored in the inner membrane with catalytic domains facing the matrix. Reason: Core cellular localization for SPG-7. UniProt annotation indicates multi-pass membrane protein topology with matrix-facing catalytic domains, consistent with m-AAA protease architecture. Supporting Evidence: UniProt:Q9N3T5 Mitochondrion inner membrane
GO:0006508 proteolysis	IEA GO_REF:0000120	ACCEPT	Summary: SPG-7 performs proteolysis as part of the m-AAA protease complex. This is the general parent term for its peptidase activity. Reason: While more specific terms exist (e.g., mitochondrial protein processing), this general proteolysis annotation is not incorrect and captures the core enzymatic activity. The IEA annotation is well-supported. Supporting Evidence: UniProt:Q9N3T5 Acts as a component of the m-AAA protease complex which is an ATP-dependent metalloprotease mediating degradation of non-assembled mitochondrial inner membrane proteins
GO:0008233 peptidase activity	IEA GO_REF:0000043	ACCEPT	Summary: General peptidase activity term. SPG-7 is indeed a peptidase, specifically a metalloendopeptidase (GO:0004222). Reason: Broad but accurate term. More specific terms (metalloendopeptidase activity, ATP-dependent peptidase activity) are also annotated, which is appropriate. Supporting Evidence: UniProt:Q9N3T5 In the C-terminal section; belongs to the peptidase M41 family
GO:0008237 metallopeptidase activity	IEA GO_REF:0000043	ACCEPT	Summary: SPG-7 is a metallopeptidase containing a zinc-dependent catalytic site. This is a parent term of metalloendopeptidase activity. Reason: Accurate intermediate-level term. SPG-7 uses zinc for catalysis. Supporting Evidence: UniProt:Q9N3T5 Binds 1 zinc ion per subunit
GO:0008270 zinc ion binding	IEA GO_REF:0000002	ACCEPT	Summary: SPG-7 binds zinc as a catalytic cofactor. UniProt identifies zinc-binding residues that coordinate the catalytic zinc ion. Reason: Correct annotation. Zinc binding is essential for SPG-7's metallopeptidase activity. The zinc ion is required for catalysis at the active site. Supporting Evidence: UniProt:Q9N3T5 Binds 1 zinc ion per subunit
GO:0016020 membrane	IEA GO_REF:0000002	ACCEPT	Summary: Very general term indicating membrane localization. SPG-7 is specifically located in the mitochondrial inner membrane. Reason: Not incorrect but very general. The more specific term GO:0005743 (mitochondrial inner membrane) is also annotated, which provides better precision. Supporting Evidence: UniProt:Q9N3T5 Multi-pass membrane protein
GO:0016787 hydrolase activity	IEA GO_REF:0000043	ACCEPT	Summary: Very general term. SPG-7 has both peptidase (protein hydrolase) and ATPase (nucleotide hydrolase) activities. Reason: Accurate high-level classification. More specific terms are also annotated.
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000002	ACCEPT	Summary: SPG-7's AAA+ ATPase domain hydrolyzes ATP to power substrate engagement and translocation. This is essential for m-AAA protease function. Reason: Core molecular function. ATP hydrolysis drives the mechanical work of unfolding substrates and translocating them into the proteolytic chamber. Supporting Evidence: UniProt:Q9N3T5 In the N-terminal section; belongs to the AAA ATPase family
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: General term for metal binding. SPG-7 specifically binds zinc. Reason: Accurate but general. More specific term (zinc ion binding, GO:0008270) is also annotated.
GO:0051604 protein maturation	IEA GO_REF:0000117	ACCEPT	Summary: SPG-7 participates in protein maturation through processing of imported mitochondrial proteins. This ARBA machine learning annotation is consistent with m-AAA protease function. Reason: Appropriate annotation. m-AAA proteases process and mature mitochondrial proteins after import, contributing to their functional maturation. Supporting Evidence: UniProt:Q9N3T5 Functions both in post-translational assembly and in the turnover of mistranslated or misfolded polypeptides
GO:0110039 positive regulation of nematode male tail tip morphogenesis	IMP PMID:21408209 A bow-tie genetic architecture for morphogenesis suggested b...	KEEP AS NON CORE	Summary: In a genome-wide RNAi screen for male tail tip morphogenesis genes, spg-7 RNAi resulted in a "Lep" (leptoderan) phenotype - retention of the pointed larval tail tip. This was identified alongside 211 other genes. The annotation represents a high-throughput screen hit rather than focused investigation of spg-7's role. Reason: This annotation is technically valid - spg-7 RNAi does cause a male tail tip morphogenesis defect. However, this is likely a pleiotropic consequence of general mitochondrial dysfunction rather than a direct role in morphogenesis. The paper identified spg-7 as one of 41 suppressors of let-7 lethality with morphogenesis phenotypes, suggesting this reflects general cellular fitness rather than a specific role in tail tip development. This should be kept but marked as non-core function. Supporting Evidence: PMID:21408209 Of the 41 suppressors of let-7 lethality identified by Ding et al. [44], six were positives in our screen. RNAi knockdown of two (pri-2, npp-6) resulted in the Ore phenotype, of two others (spg-7, smo-1) in the Lep phenotype
GO:0034982 mitochondrial protein processing	IMP PMID:22700657 Mitochondrial import efficiency of ATFS-1 regulates mitochon...	ACCEPT	Summary: Nargund et al. (2012) showed that spg-7(RNAi) causes mitochondrial stress that activates the UPRmt via ATFS-1. This demonstrates that SPG-7 is required for normal mitochondrial protein handling, and its loss leads to accumulation of misfolded proteins. Reason: Direct experimental evidence for spg-7 function in mitochondrial protein processing. Loss of spg-7 function causes nuclear accumulation of ATFS-1 and activation of UPRmt, indicating impaired mitochondrial proteostasis. Supporting Evidence: PMID:22700657 However, during mitochondrial stress, we found that import efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus UniProt:Q9N3T5 RNAi- mediated knockdown induces nuclear and mitochondrial transcription of mitochondrial protective genes including chaperone hsp-60 as part of the mitochondrial unfolded protein response
GO:0034982 mitochondrial protein processing	IMP PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista...	ACCEPT	Summary: Pellegrino et al. (2014) used spg-7(RNAi) as a tool to induce mitochondrial stress and activate the UPRmt. The paper confirms spg-7's role in mitochondrial protein quality control. Reason: Independent experimental confirmation of spg-7's role in mitochondrial protein processing. The study uses spg-7 knockdown to model mitochondrial dysfunction. Supporting Evidence: UniProt:Q9N3T5 Functions both in post-translational assembly and in the turnover of mistranslated or misfolded polypeptides
GO:0010629 negative regulation of gene expression	IMP PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista...	MODIFY	Summary: When SPG-7 is functional, it suppresses expression of stress-response genes by maintaining mitochondrial proteostasis. Loss of spg-7 leads to upregulation of UPRmt target genes and innate immune genes via ATFS-1. Reason: The annotation is technically accurate but captures an indirect effect. SPG-7 does not directly regulate gene expression - rather, its proteolytic activity maintains mitochondrial health, which in turn keeps ATFS-1 in mitochondria where it is degraded. A more appropriate annotation would be to the upstream process (mitochondrial protein processing) or the regulatory pathway. Proposed replacements: mitochondrial unfolded protein response Supporting Evidence: PMID:22700657 However, during mitochondrial stress, we found that import efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus
GO:0010468 regulation of gene expression	IGI PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista...	MODIFY	Summary: The IGI annotation with atfs-1 indicates genetic interaction - spg-7 and atfs-1 together regulate gene expression. The paper shows that spg-7(RNAi) effects on gene expression require atfs-1. Reason: Similar to the IMP annotation above, this captures an indirect effect. SPG-7 does not directly regulate gene expression but rather maintains mitochondrial proteostasis. The effects on gene expression are mediated by ATFS-1 when mitochondrial stress occurs. A more specific term would better capture the mechanism. Proposed replacements: mitochondrial unfolded protein response Supporting Evidence: UniProt:Q9N3T5 RNAi-mediated knockdown abolishes transcription up- regulation in an atfs-1 (tm4919) mutant background
GO:0050829 defense response to Gram-negative bacterium	IMP PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista...	KEEP AS NON CORE	Summary: Pellegrino et al. (2014) showed that spg-7(RNAi) pre-treatment activates the UPRmt, which in turn induces innate immune genes (abf-2, lys-2, clec-4, clec-65). This provides resistance to P. aeruginosa infection. The immune response is ATFS-1 dependent and represents a coupling of mitochondrial stress to innate immunity. Reason: This annotation reflects a downstream consequence of SPG-7 dysfunction rather than a direct role in immunity. When SPG-7 is lost, mitochondrial stress activates ATFS-1-dependent innate immune genes. While experimentally valid, this represents a stress response pathway activation rather than a core immune function of SPG-7. The core function is mitochondrial protein processing; immune activation is a consequence of its loss. Supporting Evidence: UniProt:Q9N3T5 RNAi-mediated knockdown also induces the transcription of innate immunity-related genes such as lys-2, abf-2, clec-65 and clec-4 which results in resistance to P.aeruginosa-mediated infection
GO:0050829 defense response to Gram-negative bacterium	IGI PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista...	KEEP AS NON CORE	Summary: Multiple IGI annotations exist for this term, indicating genetic interactions with various innate immunity components. These all reflect the ATFS-1-dependent coupling of mitochondrial stress to immune gene induction. Reason: Same rationale as above - the immune response is a downstream consequence of mitochondrial stress caused by loss of SPG-7 function. The core function remains mitochondrial protein processing. Supporting Evidence: UniProt:Q9N3T5 RNAi-mediated knockdown also induces the transcription of innate immunity-related genes such as lys-2, abf-2, clec-65 and clec-4 which results in resistance to P.aeruginosa-mediated infection
GO:0004222 metalloendopeptidase activity	ISS PMID:15280428 Compartment-specific perturbation of protein handling activa...	ACCEPT	Summary: ISS annotation based on similarity to human AFG3L2. The Yoneda et al. (2004) paper established spg-7 as encoding a mitochondrial protease in C. elegans, demonstrating that RNAi knockdown activates the UPRmt. Reason: The ISS annotation is well-supported. SPG-7 has conserved metalloprotease domains and sequence similarity to characterized m-AAA proteases. This annotation provides additional evidence type for the core molecular function. Supporting Evidence: UniProt:Q9N3T5 In the C-terminal section; belongs to the peptidase M41 family
GO:0005739 mitochondrion	ISS PMID:15280428 Compartment-specific perturbation of protein handling activa...	ACCEPT	Summary: ISS annotation based on similarity to mouse Afg3l2. Mitochondrial localization is well-established for m-AAA proteases. Reason: Correct cellular component annotation. While more specific terms exist (mitochondrial inner membrane), this general mitochondrial localization is accurate and useful. Supporting Evidence: UniProt:Q9N3T5 Mitochondrion inner membrane
GO:0065003 protein-containing complex assembly	IMP PMID:15280428 Compartment-specific perturbation of protein handling activa...	MODIFY	Summary: Yoneda et al. (2004) showed that RNAi of spg-7 and other mitochondrial proteases/ chaperones activates the UPRmt. This indicates a role in assembly of multi-subunit mitochondrial complexes. Reason: While the annotation reflects an indirect function, the term is too general. SPG-7's role is specifically in mitochondrial respiratory chain complex assembly and mitochondrial protein complex maturation. A more specific term would be more informative. Proposed replacements: mitochondrial respiratory chain complex assembly Supporting Evidence: UniProt:Q9N3T5 The complex is necessary for the assembly of mitochondrial respiratory chain and ATPase complexes
GO:0034514 mitochondrial unfolded protein response	IMP PMID:22700657 Mitochondrial import efficiency of ATFS-1 regulates mitochon...	NEW	Summary: SPG-7 is a key activator of the UPRmt when its function is compromised. Loss of spg-7 function leads to mitochondrial stress and activation of the UPRmt pathway via ATFS-1. This is one of the best-characterized UPRmt triggers in C. elegans. Reason: This is a well-established function of spg-7 in C. elegans not currently annotated. Multiple papers (PMID:22700657, PMID:25274306, PMID:15280428) demonstrate that spg-7(RNAi) activates the UPRmt. While SPG-7 does not directly signal in the UPRmt pathway, its loss triggers the response, making it involved in the process. Supporting Evidence: PMID:22700657 However, during mitochondrial stress, we found that import efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus UniProt:Q9N3T5 RNAi- mediated knockdown induces nuclear and mitochondrial transcription of mitochondrial protective genes including chaperone hsp-60 as part of the mitochondrial unfolded protein response
GO:0033108 mitochondrial respiratory chain complex assembly	ISS PMID:15280428 Compartment-specific perturbation of protein handling activa...	NEW	Summary: m-AAA proteases are required for assembly of mitochondrial respiratory chain complexes. This function is well-established in yeast and mammals and is conserved in C. elegans based on domain architecture and phenotypic effects. Reason: This core function is implicit in UniProt annotation but not currently in GO. UniProt states the m-AAA protease complex is necessary for the assembly of mitochondrial respiratory chain and ATPase complexes. PMID:25773600 shows spg-7(RNAi) reduces oxygen consumption, indicating respiratory defects. Supporting Evidence: UniProt:Q9N3T5 The complex is necessary for the assembly of mitochondrial respiratory chain and ATPase complexes UniProt:Q9N3T5 RNAi-mediated knockdown reduces oxygen consumption

Gene Description

Existing Annotations Review

Core Functions

ATP-dependent zinc metalloendopeptidase that degrades misfolded and unassembled mitochondrial inner membrane proteins. The proteolytic chamber is formed by the M41 peptidase domain and requires zinc for catalysis.

Processes imported mitochondrial proteins and is required for assembly of mitochondrial respiratory chain and ATPase complexes. Loss of function leads to respiratory deficiency with reduced oxygen consumption.

Maintains mitochondrial proteostasis; loss of function activates the mitochondrial unfolded protein response (UPRmt) via ATFS-1 nuclear accumulation and transcriptional upregulation of mitochondrial chaperones.

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