Affinage

ARMC3

Armadillo repeat-containing protein 3 · UniProt Q5W041

Length
872 aa
Mass
96.4 kDa
Annotated
2026-04-28
24 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARMC3 is an armadillo repeat-containing protein that functions as the mammalian ortholog of yeast Vac8, recruiting class III phosphatidylinositol 3-kinase complex I (PtdIns3K-CI) to the phagophore assembly site via its ARM domains to initiate autophagosome formation; in spermatids, this activity is essential for ribophagy, and its loss causes mitochondrial energy failure, immotile flagella, and male infertility (PMID:34705610). Loss-of-function mutations in bovine and human ARMC3 produce severely disorganized sperm flagellar ultrastructure with vacuolated midpiece mitochondria, establishing ARMC3 as required for normal sperm tail assembly and motility across mammals (PMID:26923438, PMID:39221575). A homozygous splice site variant in ARMC3 has also been linked to non-syndromic stuttering in a human family, although no neuronal mechanism has been demonstrated (PMID:36553564).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2006 Low

    Before any functional data existed, cloning of human ARMC3 established that it encodes an ARM-domain-containing protein with multiple splice variants showing broad tissue expression including testis, resolving its basic gene structure.

    Evidence cDNA cloning from human fetal brain and RT-PCR across human tissues

    PMID:16915934

    Open questions at the time
    • No functional assay performed; expression data alone
    • Protein-protein interactions unknown
    • No disease or phenotypic link established
  2. 2016 Medium

    A bovine frameshift mutation truncating ARMC3 by ~46% was causally linked to a tail stump sperm defect, providing the first evidence that ARMC3 is required for sperm flagellar integrity and male fertility.

    Evidence Homozygosity mapping, whole-genome re-sequencing, genotyping segregation, and spermatozoa morphological analysis in affected bulls

    PMID:26923438

    Open questions at the time
    • No direct molecular mechanism explaining how ARMC3 loss disorganizes flagella
    • Functional rescue experiment not performed
    • Whether ARMC3 acts cell-autonomously in spermatids not determined
  3. 2021 Medium

    Identification of ARMC3 as the mammalian Vac8 ortholog resolved the mechanistic question of how ARMC3 supports spermatogenesis: its ARM domains recruit PtdIns3K-CI to the phagophore assembly site to initiate autophagy, and its deletion blocks ribophagy in spermatids, explaining mitochondrial energy failure and flagellar immotility.

    Evidence Armc3 knockout mice, functional complementation with yeast Vac8, autophagy flux assays, and electron microscopy of spermatids

    PMID:34705610

    Open questions at the time
    • Single-lab study; independent replication needed
    • Structural basis of ARMC3-PtdIns3K-CI interaction not resolved
    • Whether ARMC3 mediates autophagy outside spermatids (e.g., somatic tissues) not tested
  4. 2022 Low

    A splice site variant in human ARMC3 was linked to non-syndromic stuttering, raising the question of whether ARMC3 has a neurodevelopmental role beyond spermatogenesis.

    Evidence Whole-exome sequencing and segregation analysis in a consanguineous Pakistani family

    PMID:36553564

    Open questions at the time
    • No neuronal mechanism demonstrated; genetic association only in a single family
    • Same splice variant later confirmed to abolish ARMC3 protein in sperm but neuronal expression/function not assessed
    • No replication cohort for the stuttering phenotype
  5. 2024 Medium

    Protein-level confirmation in human sperm that the c.916+1G>A splice variant abolishes ARMC3 expression and causes flagellar ultrastructural defects with mitochondrial vacuolation validated the bovine and mouse findings in humans, establishing ARMC3 loss-of-function as a cause of human asthenozoospermia.

    Evidence Whole-exome sequencing, RT-PCR, Western blot on patient sperm, and transmission electron microscopy

    PMID:39221575

    Open questions at the time
    • Single family; larger cohort studies needed to establish population-level relevance
    • Whether autophagy/ribophagy defect underlies the human flagellar phenotype not directly tested
    • Functional rescue not attempted

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of ARMC3–PtdIns3K-CI interaction, whether ARMC3-mediated autophagy operates in somatic tissues, and whether the neurodevelopmental association with stuttering reflects a genuine ARMC3 function or a coincidental variant in a single pedigree.
  • No structural or biophysical characterization of ARMC3-PtdIns3K-CI binding
  • Somatic autophagy role untested in vivo
  • Neuronal expression and function of ARMC3 uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1474165 Reproduction 3 R-HSA-9612973 Autophagy 1
Partners
BECN1PIK3C3

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 Mouse ARMC3 was identified as the functional homolog of yeast Vac8; its ARM domains recruit class III phosphatidylinositol 3-kinase complex I (PtdIns3K-CI) to the phagophore assembly site (PAS) to initiate autophagosome formation, and deletion of Armc3 in mice blocked ribophagy in spermatids, causing low mitochondrial energy levels, immotile flagella, and male infertility. Mouse Armc3 knockout, functional complementation with yeast Vac8 assays, autophagy flux assays, electron microscopy of spermatids Autophagy Medium 34705610
2016 A frameshift mutation in bovine ARMC3 (p.A451fs26) causing premature translation termination and loss of 46% of the protein including C-terminal domains was causally associated with a tail stump sperm defect characterized by severely disorganized, immotile spermatozoa tails, establishing ARMC3 as required for normal sperm tail/flagellar structure. Homozygosity mapping, whole-genome re-sequencing, genotyping of affected vs. unaffected bulls, morphological analysis of spermatozoa BMC genetics Medium 26923438
2024 A homozygous ARMC3 splicing variant (c.916+1G>A) causing exon 8 skipping and a predicted truncated protein (p.Glu245_Asp305delfs*16) abolishes ARMC3 protein expression in sperm (confirmed by Western blot), leading to reduced sperm motility and disrupted flagellar ultrastructure including vacuolation of sperm mitochondria at the midpiece. Whole-exome sequencing, RT-PCR, Western blot of patient sperm, transmission electron microscopy of sperm ultrastructure Clinical genetics Medium 39221575
2006 Human ARMC3 produces at least two splice variants (ARMC3_v1 and ARMC3_v2) with distinct tissue expression patterns; ARMC3_v2 encodes a 688-amino acid protein containing three ARM domains, expressed in skeletal muscle, liver, spleen, and thymus, while ARMC3_v1 is expressed in skeletal muscle, lung, prostate, and testis. cDNA cloning from human fetal brain, RT-PCR across human tissues Genetika Low 16915934
2022 A homozygous splice site variant in human ARMC3 (c.916+1G>A) causing exon 8 skipping was identified as causing non-syndromic stuttering in a consanguineous Pakistani family, expanding ARMC3's role to neurodevelopmental function. Whole-exome sequencing, segregation analysis in consanguineous family, splice prediction Genes Low 36553564

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 YEB3/VAC8 encodes a myristylated armadillo protein of the Saccharomyces cerevisiae vacuolar membrane that functions in vacuole fusion and inheritance. Journal of cell science 65 9664035
2005 The DHHC protein Pfa3 affects vacuole-associated palmitoylation of the fusion factor Vac8. Proceedings of the National Academy of Sciences of the United States of America 51 16301533
2009 Molecular recognition of the palmitoylation substrate Vac8 by its palmitoyltransferase Pfa3. The Journal of biological chemistry 45 19416974
2006 Palmitoylation determines the function of Vac8 at the yeast vacuole. Journal of cell science 43 16720644
2016 A frameshift mutation in ARMC3 is associated with a tail stump sperm defect in Swedish Red (Bos taurus) cattle. BMC genetics 34 26923438
2020 Vac8 determines phagophore assembly site vacuolar localization during nitrogen starvation-induced autophagy. Autophagy 27 32508216
2023 The Atg1 complex, Atg9, and Vac8 recruit PI3K complex I to the pre-autophagosomal structure. The Journal of cell biology 26 37436710
2006 Candida albicans VAC8 is required for vacuolar inheritance and normal hyphal branching. Eukaryotic cell 25 16467476
2006 Role of Vac8 in formation of the vacuolar sequestering membrane during micropexophagy. Autophagy 24 16874085
2019 Quaternary structures of Vac8 differentially regulate the Cvt and PMN pathways. Autophagy 20 31512555
2005 ATP-independent control of Vac8 palmitoylation by a SNARE subcomplex on yeast vacuoles. The Journal of biological chemistry 19 15701652
2019 The carboxy terminus of yeast Atg13 binds phospholipid membrane via motifs that overlap with the Vac8-interacting domain. Autophagy 16 31352862
2006 Early and late molecular events of glucose-induced pexophagy in Pichia pastoris require Vac8. Autophagy 16 16921262
2023 Chemical Complementarity of Breast Cancer Resident, T-Cell Receptor CDR3 Domains and the Cancer Antigen, ARMC3, is Associated With Higher Levels of Survival and Granzyme Expression. Cancer informatics 13 37313373
2019 Vac8 Controls Vacuolar Membrane Dynamics during Different Autophagy Pathways in Saccharomyces cerevisiae. Cells 13 31262095
2024 A homozygous ARMC3 splicing variant causes asthenozoospermia and flagellar disorganization in a consanguineous family. Clinical genetics 10 39221575
2021 A conserved Vac8/ARMC3-PtdIns3K-CI cascade regulates autophagy initiation and functions in spermiogenesis by promoting ribophagy. Autophagy 10 34705610
2023 Structures of Vac8-containing protein complexes reveal the underlying mechanism by which Vac8 regulates multiple cellular processes. Proceedings of the National Academy of Sciences of the United States of America 7 37094131
2022 The Expansion of the Spectrum in Stuttering Disorders to a Novel ARMC Gene Family (ARMC3). Genes 6 36553564
2006 Cloning and expression of ARMC3_v2, a novel splicing variant of the human ARMC3 gene. Genetika 3 16915934
2024 The emerging significance of Vac8, a multi-purpose armadillo-repeat protein in yeast. Autophagy 2 39045779
2025 The vacuolar protein 8 (Vac8) homolog in Cryptococcus neoformans plays conserved and unique roles in vacuolar and cellular morphology, impacting important stress responses and virulence traits. bioRxiv : the preprint server for biology 0 40661350
2025 The Vacuolar Protein 8 (Vac8) Homolog in Cryptococcus neoformans Impacts Stress Responses and Virulence Traits Through Conserved and Unique Roles. Journal of fungi (Basel, Switzerland) 0 41440702
2023 Erratum to "Chemical Complementarity of Breast Cancer Resident, T-Cell Receptor CDR3 Domains and the Cancer Antigen, ARMC3, is Associated With Higher Levels of Survival and Granzyme Expression". Cancer informatics 0 37465006