VPS37A

VPS37A is a core subunit of the mammalian ESCRT-I complex that functions in both endosomal sorting and autophagosome biogenesis. Through its mod(r) domain, VPS37A assembles with Tsg101 and VPS28 on late endosomes to drive lysosomal degradation of ubiquitinated membrane receptors including EGFR, TNFR1, and the glucagon receptor, with hepatocyte-specific loss causing endosomal accumulation of the glucagon receptor and overactivation of cAMP/PKA/CREB-dependent gluconeogenesis (PMID:15240819, PMID:36243006, PMID:40746890). Independently of its ESCRT-I assembly function, VPS37A uses its N-terminal ubiquitin E2 variant-like (UEVL) domain to localize to the phagophore, where it recruits VPS28 and the ESCRT-III subunit CHMP2A to mediate VPS4-dependent phagophore closure; loss of UEVL function blocks autophagosome completion, causes TBK1 accumulation on unclosed phagophores, and drives p62 hyperphosphorylation and inclusion body formation (PMID:31519728, PMID:39607828).

1. 2004 High

   Identification of VPS37A as a bona fide ESCRT-I subunit resolved how a then-uncharacterized protein (HCRP1) links the upstream Hrs/STAM machinery to the Tsg101–VPS28 core complex and established its requirement for lysosomal degradation of EGF receptors.

   Evidence Reciprocal co-IP, size-exclusion co-fractionation, colocalization on LAMP1-positive endosomes, and siRNA knockdown showing impaired EGFR degradation in human cells

   PMID:15240819

   Open questions at the time

   • Structural basis of the mod(r)-mediated interaction with Tsg101 not resolved
   • Whether VPS37A has functions beyond the MVB pathway was unknown
   • No information on receptor specificity beyond EGFR
2. 2019 High

   A genome-wide CRISPR screen revealed that VPS37A's role extends beyond endosomal sorting to phagophore closure during autophagy, and domain dissection showed that the N-terminal UEV domain is required for phagophore localization and ESCRT-III recruitment but dispensable for ESCRT-I complex formation.

   Evidence FACS-based HaloTag-LC3 autophagosome completion screen, UEV deletion mutants, epistasis with CHMP2A and VPS4, live imaging in human cells

   PMID:31519728

   Open questions at the time

   • Identity of the phagophore receptor or lipid determinant recognized by the UEV domain unknown
   • Downstream signaling consequences of failed phagophore closure not addressed
3. 2022 High

   Extending VPS37A's endosomal function to metabolic physiology, hepatocyte-specific knockdown demonstrated that VPS37A controls the spatiotemporal localization of the glucagon receptor, uncoupling gluconeogenesis from β-oxidation in vivo.

   Evidence Cy5-glucagon trafficking, hepatocyte-specific siRNA in mice, cAMP/PKA/p-CREB signaling readouts, receptor re-localization rescue

   PMID:36243006

   Open questions at the time

   • Whether VPS37A similarly regulates other hepatocyte GPCRs is untested
   • Mechanism by which glucagon receptor is preferentially retained in endosomes upon VPS37A loss not defined
4. 2024 High

   An in vivo knock-in model pinpointed the UEVL domain (β-strands 43–139) as the autophagy-specific module of VPS37A and revealed that failed phagophore closure leads to TBK1 accumulation on open phagophores, enhanced p62 phosphorylation, and inclusion body formation—linking ESCRT-mediated membrane sealing to innate immune kinase signaling.

   Evidence UEVL-deletion knock-in mice, LC3 BioID proximity proteomics, autophagic flux and p62/ubiquitin accumulation assays, TBK1 activity measurements

   PMID:39607828

   Open questions at the time

   • How TBK1 is activated by open phagophores is mechanistically unclear
   • Whether the inclusion body phenotype leads to neurodegeneration or tissue pathology in vivo not established
   • No structural model of UEVL domain at atomic resolution
5. 2025 Medium

   VPS37A was shown to direct TNFR1 to lysosomal degradation via the autophagy-lysosomal pathway, suppressing NF-κB signaling in colorectal cancer cells under metabolic stress, broadening the receptor repertoire controlled by VPS37A.

   Evidence VPS37A overexpression, RNA-seq, NF-κB luciferase reporter, lysosomal inhibition, xenograft assays

   PMID:40746890

   Open questions at the time

   • Whether TNFR1 degradation uses the MVB or autophagy arm of VPS37A function not distinguished
   • Single-lab study; awaits independent confirmation

• The phagophore-targeting mechanism of the UEVL domain remains unresolved: neither the membrane determinant (lipid species or protein receptor) recognized by the UEVL domain nor the structural basis for selective phagophore versus endosome engagement has been identified.
• No binding partner or lipid ligand identified for the UEVL domain on the phagophore
• No high-resolution structure of VPS37A UEVL domain available
• In vivo physiological consequences of UEVL loss (beyond TBK1/p62) in disease models not characterized