ATP6V1C2 (V-type proton ATPase subunit C 2) review notes

UniProt: Q8NEY4 (VATC2_HUMAN), 427 AA. Gene HGNC:18264, chromosome 2.

Identity and family

• ATP6V1C2 encodes the "C" subunit of the V1 peripheral domain of the vacuolar
  H+-ATPase (V-ATPase), a multisubunit rotary proton pump. It is one of two human
  paralogs of subunit C (the other being ATP6V1C1) [file:human/ATP6V1C2/ATP6V1C2-uniprot.txt
  "Belongs to the V-ATPase C subunit family"].
• The protein was cloned as a tissue-specific isoform of the human V-ATPase C subunit
  PMID:12384298.
• Two splice isoforms exist: Q8NEY4-1 (displayed, 427 AA) and Q8NEY4-2 (VSP_024883,
  residues 276-321 missing) [file:human/ATP6V1C2/ATP6V1C2-uniprot.txt ALTERNATIVE PRODUCTS].

Molecular function and structural role

• Subunit C of V-ATPase sits at the interface between the catalytic V1 head and the
  membrane-embedded V0 sector, as part of/anchoring the peripheral stator stalk. UniProt:
  "Subunit C is necessary for the assembly of the catalytic sector of the enzyme and is
  likely to have a specific function in its catalytic activity"
  [file:human/ATP6V1C2/ATP6V1C2-uniprot.txt FUNCTION, By similarity to P21282/P21283/P31412].
• The V1 complex "consists of three catalytic AB heterodimers ... three peripheral stalks
  each consisting of EG heterodimers, one central rotor including subunits D and F, and the
  regulatory subunits C and H" [file:human/ATP6V1C2/ATP6V1C2-uniprot.txt SUBUNIT].
• Subunit C is a key regulator of reversible V1-V0 assembly/disassembly: it is released from
  both V1 and V0 when the holoenzyme disassembles, and re-binding of subunit C is required for
  reassembly (well established for yeast Vma5p and the mammalian ortholog; the human protein is
  annotated By similarity). This makes subunit C a regulatory hub for controlling V-ATPase
  activity in response to signals.
• The protein is a structural/regulatory subunit; it does not itself hydrolyze ATP or
  translocate protons, but participates in the rotary catalytic mechanism as part of the V1
  domain. GO_Central IBA assigns enables proton-transporting ATPase activity, rotational
  mechanism (GO:0046961) to the whole C-subunit family by descent
  [file:human/ATP6V1C2/ATP6V1C2-goa.tsv IBA GO_REF:0000033].

Localization

• As a V1 subunit, it is cytosolic/peripheral-membrane-associated; the free pool of subunit C
  (after disassembly) is cytosolic [Reactome TAS GO:0005829 cytosol].
• Detected by proteomics in lysosomal membrane fractions of human placenta
  PMID:17897319 - consistent with V-ATPase residing on the lysosomal/endolysosomal membrane.
• Detected in human urinary exosomes by large-scale proteomics
  PMID:19056867 - a high-throughput catalog hit, not evidence of a primary
  exosomal function.

Physiological roles / pathway context

• V-ATPase acidifies intracellular compartments (endosomes, lysosomes, Golgi, secretory
  vesicles) and, in some cells, the extracellular space; ATP6V1C2 contributes to this as a
  V1 subunit [file:human/ATP6V1C2/ATP6V1C2-uniprot.txt FUNCTION].
• V-ATPase-mediated acidification is required for Wnt/beta-catenin signaling; the prorenin
  receptor (ATP6AP2/PRR) acts as an adaptor between Wnt receptors and the V-ATPase complex
  PMID:20093472. The IMP annotation of
  GO:0030177 (positive regulation of Wnt signaling) to ATP6V1C2 derives from this work; it
  reflects a downstream consequence of V-ATPase acidification rather than a subunit-specific
  Wnt function. Keep as non-core.
• A NAS annotation links the gene to regulation of macroautophagy via PMID:22982048, a study of
  lipofuscin formation and lysosomal/autophagy activity in senescent fibroblasts
  PMID:22982048. This paper does not establish a direct ATP6V1C2 role in autophagy regulation;
  the link is indirect (V-ATPase dependent lysosomal acidification supports autophagic
  degradation). Keep as non-core / over-annotation.
• Reactome maps the protein into many acidification and mTORC1-amino-acid-sensing reactions
  (endosome acidification, phagosomal pH lowering, transferrin recycling, v-ATPase:Ragulator
  signaling), all consistent with general V-ATPase function; the associated GO annotations are
  all cytosol (GO:0005829) location calls.

Tissue specificity

• Originally reported as kidney and placenta enriched [file:human/ATP6V1C2/ATP6V1C2-uniprot.txt
  TISSUE SPECIFICITY, PubMed:12384298]; HPA reports tissue-enhanced expression in epididymis,
  salivary gland and skin. Often described as the lung/kidney-enriched isoform relative to the
  ubiquitous ATP6V1C1.

Annotation assessment summary

• ACCEPT core: GO:0046961 (proton-transporting ATPase activity, rotational mechanism, IBA),
  GO:0033180 (V1 domain part_of, IEA) as a structural membership term, GO:1902600 (proton
  transmembrane transport).
• GO:0015078 (proton transmembrane transporter activity, IEA): broad InterPro transfer;
  subunit C is not itself the transporter. Mark as over-annotated / keep as non-core.
• GO:0042802 (identical protein binding, IPI from PMID:21356312): the cited paper expressed and
  purified isoforms including C2 but the abstract does not demonstrate C2 self-association; this
  is an uninformative binding term. Mark as over-annotated.
• GO:0030177 (positive regulation of Wnt signaling, IMP): indirect/pathway-level; keep as
  non-core.
• GO:0016241 (regulation of macroautophagy, NAS): weakly supported, indirect; mark as
  over-annotated.
• GO:0070062 (extracellular exosome, HDA): proteomic catalog hit; mark as over-annotated.
• GO:0005765 (lysosomal membrane, HDA): consistent with V-ATPase localization; keep as
  non-core.
• GO:0005829 (cytosol, TAS Reactome, x12): valid for the free/peripheral V1 pool; keep as
  non-core (representative).

Falcon deep research synthesis (2026-06-21)

Falcon deep research has now completed (file:human/ATP6V1C2/ATP6V1C2-deep-research-falcon.md,
18 citations). It corroborates the C2 (tissue-restricted C-subunit paralog) biology
above and sharpens the expression/role picture; no change to annotation calls.

• Core confirmed. C2 is a single-copy regulatory/stator V1 subunit (paralog of
  ubiquitous C1), part of the collar coupling A3B3 ATP hydrolysis to rotor-driven
  proton translocation and required for V1 assembly — not catalytic itself.
• Expression refined to the renal "ionocyte" program. Single-cell data place
  ATP6V1C2 predominantly in type-A (acid-secretory) intercalated cells of the
  collecting duct, part of the conserved FOXI1+ ionocyte family that also expresses
  ATP6V1B1 and KRT7 (Casellas 2023; Jobst-Schwan 2020). This supports a
  kidney-acid-secretion functional context for C2 (consistent with the
  kidney/lung-enriched framing in the notes; not testis-specific).
• Functional role. In intercalated cells, apical V-ATPase (containing C2)
  secretes carbonic-anhydrase-II–derived H+ into the lumen (with basolateral
  AE1/SLC4A1 exporting HCO3-), contributing to systemic acid-base balance;
  type-A intercalated-cell number/V-ATPase activity adapts to acid loading via
  FOXI1/TFCP2L1/NOTCH. Renal-physiology context (the molecular function remains the
  generic V1 C-subunit assembly/regulatory role).

Net: no change to calls — C2 is the tissue-restricted (renal intercalated cell)
regulatory C-subunit paralog supporting V-ATPase assembly and acid secretion.