VPS37B

VPS37B is a core subunit of the heterotetrameric ESCRT-I complex (with TSG101, VPS28, and MVB12A/B), functioning in endosomal sorting, multivesicular body biogenesis, autophagosome closure, and enveloped virus budding. The crystal structure of the ESCRT-I headpiece containing VPS37B reveals a helical filament with a 12-molecule repeat that is essential for membrane scission events including autophagosome closure and HIV-1 release (PMID:32424346). VPS37B binds TSG101 at multiple sites, recruits ESCRT-I activity to endosomes, interacts with the Ca²⁺-dependent adaptor ALG-2 to bridge ALIX to ESCRT-I, and cooperates with SH3YL1 to direct EGFR sorting into multivesicular bodies for lysosomal degradation (PMID:15218037, PMID:23924735, PMID:31492760). Loss of VPS37B, together with paralogs VPS37A/C, destabilizes the ESCRT-I complex and activates p21/NF-κB-dependent growth arrest and sterile inflammation, and disruption of VPS37A/B in dendritic cells impairs mannose receptor endocytosis and downstream Th2 immune responses (PMID:33419951, PMID:33895493).

1. 2004 High

   Identification of VPS37B as a stoichiometric ESCRT-I subunit that binds TSG101 at multiple sites and functions in HIV-1 budding established it as a core component of the class E VPS pathway.

   Evidence Co-IP, yeast two-hybrid, gel filtration, functional rescue of HIV-1 Gag budding, dominant-negative VPS4A trapping in human cells

   PMID:15218037 PMID:15509564

   Open questions at the time

   • Structural basis of VPS37B–TSG101 interaction not yet resolved
   • Redundancy with VPS37A and VPS37C not fully delineated
   • Endogenous cargo sorting role not demonstrated
2. 2007 Medium

   Demonstration that Ebola VP40 can redirect VPS37B from endosomes to the plasma membrane independently of TSG101 interaction broadened VPS37B's role beyond HIV to filovirus budding.

   Evidence VP40 deletion analysis, VLP release assay, confocal microscopy

   PMID:17940959

   Open questions at the time

   • Direct binding interface between VP40 and VPS37B not mapped
   • No confirmation of requirement for VPS37B specifically (versus other VPS37 paralogs) in Ebola budding
3. 2013 Medium

   Discovery that ALG-2 acts as a Ca²⁺-dependent bridge between VPS37B-containing ESCRT-I and ALIX revealed a regulatory layer linking calcium signaling to ESCRT assembly.

   Evidence Far-Western blot, pulldown with recombinant proteins, in vitro binding with purified components

   PMID:23924735

   Open questions at the time

   • Physiological contexts in which Ca²⁺-dependent ESCRT-I/ALIX coupling is rate-limiting remain undefined
   • No in vivo validation of the ternary complex
4. 2019 Medium

   Showing that SH3YL1 binds VPS37B via its SH3 domain to promote EGFR sorting into MVBs established VPS37B as a direct participant in receptor tyrosine kinase downregulation.

   Evidence Co-IP, siRNA knockdown, EGF trafficking and EGFR degradation assays

   PMID:31492760

   Open questions at the time

   • Whether the SH3YL1–VPS37B interaction is direct or bridged through other ESCRT-I subunits not fully resolved
   • Generalizability to other receptor cargoes unknown
5. 2020 High

   Solving the crystal structure of the ESCRT-I headpiece (TSG101–VPS28–VPS37B–MVB12A) revealed a helical filament architecture required for membrane scission in autophagosome closure and HIV-1 release, providing the first structural framework for VPS37B within the complex.

   Evidence X-ray crystallography, electron microscopy, mutagenesis, autophagosome closure and HIV-1 release functional assays

   PMID:32424346

   Open questions at the time

   • Specific contacts contributed by VPS37B to helical assembly versus those from other subunits not individually dissected
   • How helical ESCRT-I filaments coordinate with downstream ESCRT-III in vivo remains unclear
6. 2021 Medium

   Multiple studies in 2021 expanded VPS37B's functional repertoire: its loss (with paralogs) destabilizes ESCRT-I triggering p21/NF-κB stress responses, it enables mannose receptor endocytosis in dendritic cells affecting Th2 immunity, and it selectively associates with the pro-apoptotic factor CDIP1 via ALG-2.

   Evidence siRNA/CRISPR knockdown, transcriptomics, western blotting, Co-IP with CDIP1, caspase activity assays, dendritic cell co-culture and mouse allergic rhinitis model

   PMID:33419951 PMID:33503978 PMID:33895493

   Open questions at the time

   • Whether VPS37B has non-redundant roles distinct from VPS37A/C in any physiological context is not established
   • Mechanism by which ESCRT-I destabilization activates NF-κB is indirect and not molecularly defined
   • CDIP1–VPS37B association demonstrated by single Co-IP approach without reciprocal or endogenous validation

• It remains unknown whether VPS37B has non-redundant, paralog-specific functions in vivo, what structural determinants within VPS37B specify its preferential interactions with ALG-2/CDIP1, and how VPS37B contributes to ESCRT-I filament assembly at the residue level.
• No single-gene VPS37B knockout phenotype characterized in animal models
• No mutagenesis of VPS37B-specific residues within the helical ESCRT-I filament
• Post-translational regulation of VPS37B is uncharacterized