ARMC3 is an armadillo-repeat protein expressed mainly in testis and brain. In mouse spermatids it is required for autophagic degradation of cytosolic ribosomes (ribophagy), which supplies energy for mitochondria and flagellar beating. Armc3-null male mice are infertile with immotile sperm. Men homozygous for an ARMC3 splice-site variant have asthenozoospermia, with disrupted flagellar ultrastructure and vacuolated midpiece mitochondria, and a truncating ARMC3 variant in cattle causes a tail-stump sperm defect. Mouse ARMC3 is reported to recruit class III PI3-kinase complex I to the phagophore, as its proposed yeast counterpart Vac8 does, although PANTHER places ARMC3 and Vac8 in different families.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0007286 spermatid development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Spermatid development (ISS, from mouse Armc3). Armc3 loss causes male infertility with immotile spermatid flagella, but as a consequence of failed ribophagy rather than through a direct role in spermatid differentiation. Broad developmental term; kept as non-core. Reason: [PMID:34428398 "Mice lacking ARMC3 have normal viability but show complete male infertility."] [PMID:34428398 "Proteomic analysis indicated that the autophagic degradation of cytosolic ribosomes was blocked in ARMC3-deficient spermatids, which caused low energy levels of mitochondria and motionless flagella."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2AU72 SUPPORTS TRANSFER Mouse Armc3 (UniProtKB:A2AU72); donor IMP from the knockout study (PMID:34428398); human biallelic loss gives a matching sperm phenotype (PMID:39221575). Supporting Evidence: PMID:34428398 Mice lacking ARMC3 have normal viability but show complete male infertility. PMID:34428398 Proteomic analysis indicated that the autophagic degradation of cytosolic ribosomes was blocked in ARMC3-deficient spermatids, which caused low energy levels of mitochondria and motionless flagella. |
| GO:0030317 flagellated sperm motility | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Flagellated sperm motility (ISS, from mouse Armc3). Motility is lost in Armc3-null mice and reduced in men with biallelic ARMC3 loss. It is secondary to the energy deficit from blocked ribophagy, so kept as non-core. Reason: [PMID:34428398 "Proteomic analysis indicated that the autophagic degradation of cytosolic ribosomes was blocked in ARMC3-deficient spermatids, which caused low energy levels of mitochondria and motionless flagella."] [PMID:39221575 "Individuals homozygous for the ARMC3 splicing variant displayed reduced sperm motility with frequent morphological abnormalities of sperm flagella."] [PMID:39221575 "Transmission electron microscopy of the affected individual IV: 2 revealed vacuolation in sperm mitochondria at the midpiece and disrupted flagellar ultrastructure in the principal and end piece."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2AU72 SUPPORTS TRANSFER Mouse Armc3 (UniProtKB:A2AU72); donor IMP from the knockout study (PMID:34428398); human biallelic loss gives a matching sperm phenotype (PMID:39221575). Supporting Evidence: PMID:34428398 Proteomic analysis indicated that the autophagic degradation of cytosolic ribosomes was blocked in ARMC3-deficient spermatids, which caused low energy levels of mitochondria and motionless flagella. PMID:39221575 Individuals homozygous for the ARMC3 splicing variant displayed reduced sperm motility with frequent morphological abnormalities of sperm flagella. PMID:39221575 Transmission electron microscopy of the affected individual IV: 2 revealed vacuolation in sperm mitochondria at the midpiece and disrupted flagellar ultrastructure in the principal and end piece. |
| GO:0034517 ribophagy | ISS GO_REF:0000024 | ACCEPT | Summary: Ribophagy (ISS, from mouse Armc3). Armc3-null spermatids fail to degrade cytosolic ribosomes by autophagy, which leaves their mitochondria short of energy and their flagella immotile. Men homozygous for an ARMC3 splice-site variant have asthenozoospermia with vacuolated midpiece mitochondria. This is ARMC3's best-supported process; accepted as core. Reason: [PMID:34428398 "Proteomic analysis indicated that the autophagic degradation of cytosolic ribosomes was blocked in ARMC3-deficient spermatids, which caused low energy levels of mitochondria and motionless flagella."] [PMID:39221575 "Individuals homozygous for the ARMC3 splicing variant displayed reduced sperm motility with frequent morphological abnormalities of sperm flagella."] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:A2AU72 SUPPORTS TRANSFER Mouse Armc3 (UniProtKB:A2AU72); donor IMP from the knockout study (PMID:34428398); human biallelic loss gives a matching sperm phenotype (PMID:39221575). Supporting Evidence: PMID:34428398 Proteomic analysis indicated that the autophagic degradation of cytosolic ribosomes was blocked in ARMC3-deficient spermatids, which caused low energy levels of mitochondria and motionless flagella. PMID:39221575 Individuals homozygous for the ARMC3 splicing variant displayed reduced sperm motility with frequent morphological abnormalities of sperm flagella. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Extracellular exosome (HDA, urinary exosome proteome). A single proteomic detection with no functional follow-up, for a protein whose known role is in spermatid autophagy; kept as non-core. Reason: [PMID:19056867 "Here, we used LC-MS/MS to profile the proteome of human urinary exosomes."] Supporting Evidence: PMID:19056867 Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. |
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Download this section (compressed HTML)Q: Is ARMC3 a true functional counterpart of yeast Vac8 despite belonging to a different PANTHER family? Does it bind class III PI3K complex I directly, and where in the spermatid is it anchored?
Experiment: Localize endogenous ARMC3 in human spermatids and test direct binding of its ARM domain to ATG14 and PIK3C3 with purified proteins.
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