VPS37B

VPS37B is a core subunit of the human ESCRT-I complex, where together with TSG101, VPS28, and an MVB12 subunit it forms a heterotetrameric headpiece that polymerizes into a helical filament with a 12-molecule repeat, conferring an essential scaffolding role required for autophagosome closure and HIV-1 release (PMID:15218037, PMID:32424346). It engages TSG101 at multiple interfaces, including a putative coiled-coil region and a PTAP motif, and its incorporation into ESCRT-I supports ubiquitinated cargo sorting and enveloped virus budding (PMID:15218037). VPS37B serves as the ESCRT-I docking point for SH3YL1, an interaction mediated by the SH3YL1 C-terminal SH3 domain that is needed for EGFR sorting into multivesicular bodies and its subsequent degradation (PMID:31492760). Through the Ca2+-dependent adaptor ALG-2, VPS37B-containing ESCRT-I is bridged to ALIX and preferentially recruits the pro-apoptotic effector CDIP1, enhancing caspase-3/7-mediated cell death (PMID:23924735, PMID:33503978). VPS37B is partially redundant with its paralog VPS37C in ESCRT-I-dependent budding, and concurrent loss of VPS37 proteins destabilizes ESCRT-I and triggers p21-mediated proliferation arrest and a sterile NF-κB inflammatory response (PMID:15509564, PMID:33419951). Functionally, VPS37B also operates in the endocytic uptake of the mannose receptor in dendritic cells, contributing to allergen recognition and Th2 responses (PMID:33895493).

1. 2004 High

   Established VPS37B as a bona fide ESCRT-I subunit, answering whether it physically integrates into the TSG101/VPS28 machinery and participates in membrane budding.

   Evidence Reciprocal Co-IP, yeast two-hybrid, size-exclusion chromatography, dominant-negative VPS4A trapping, and HIV-1 Gag budding rescue in human cells

   PMID:15218037

   Open questions at the time

   • Stoichiometry and architecture of the assembled complex not resolved at this stage
   • Cargo specificity of VPS37B-containing ESCRT-I not defined
2. 2004 Medium

   Showed that VPS37B and its paralog VPS37C are functionally overlapping within ESCRT-I, explaining why single depletion gives partial phenotypes.

   Evidence siRNA knockdown of VPS37B and VPS37C with virus-like particle release readout

   PMID:15509564

   Open questions at the time

   • Degree of redundancy with VPS37A/VPS37D not addressed
   • Distinct vs shared cargo for each paralog not mapped
3. 2007 Medium

   Revealed a TSG101-independent route for VPS37B recruitment to the plasma membrane, showing that viral matrix proteins can co-opt VPS37B directly.

   Evidence Ebola VP40 deletion analysis, VLP release assay, and confocal microscopy

   PMID:17940959

   Open questions at the time

   • Molecular interface for the TSG101-independent recruitment not identified
   • Single virus context, generality unknown
4. 2013 Medium

   Identified ALG-2 as a Ca2+-dependent adaptor that preferentially bridges VPS37B-containing ESCRT-I to ALIX, defining how this isoform-specific complex is linked to ALIX-dependent functions.

   Evidence Far-Western blot, co-expression pulldown, and in vitro binding with purified recombinant proteins

   PMID:23924735

   Open questions at the time

   • Cellular consequence of the ESCRT-I/ALIX/ALG-2 ternary complex not yet established here
   • Binding site on VPS37B-ESCRT-I not mapped
5. 2019 Medium

   Placed VPS37B as the ESCRT-I docking point for SH3YL1 in receptor downregulation, linking the subunit to EGFR sorting and degradation.

   Evidence Co-IP, SH3 domain pulldown, and SH3YL1 knockout cells with EGF trafficking and EGFR degradation readouts

   PMID:31492760

   Open questions at the time

   • Whether SH3YL1 binding requires intact ESCRT-I assembly not tested
   • Structural basis of the SH3-VPS37B interaction unknown
6. 2020 High

   Defined the structural basis of ESCRT-I function, showing the TSG101-VPS28-VPS37B-MVB12A headpiece polymerizes into a helical filament essential for autophagosome closure and viral release.

   Evidence X-ray crystallography, negative-stain EM, interface mutagenesis, in vitro filament assay, and cellular autophagosome closure and HIV-1 release assays

   PMID:32424346

   Open questions at the time

   • Specific contribution of VPS37B (vs other VPS37 paralogs) to filament geometry not isolated
   • Regulation of filament assembly in vivo not defined
7. 2021 Medium

   Demonstrated that VPS37 proteins are non-redundant stabilizers of ESCRT-I whose combined loss produces defined stress signaling, linking complex integrity to proliferation control and inflammation.

   Evidence Individual and combined siRNA knockdown, transcriptomics, Western blot for ESCRT-I stability, proliferation and NF-κB reporter assays in colorectal cancer cells

   PMID:33419951

   Open questions at the time

   • Direct trigger linking ESCRT-I destabilization to p21 and NF-κB not mechanistically resolved
   • VPS37B-specific contribution vs VPS37A/C not separated
8. 2021 Medium

   Connected VPS37B-containing ESCRT-I to programmed cell death by showing ALG-2-dependent recruitment of CDIP1 enhances caspase activation.

   Evidence Co-IP of GFP-CDIP1 with isoform-specific ESCRT-I complexes and caspase-3/7 activity assays in HEK293 cells

   PMID:33503978

   Open questions at the time

   • Physiological setting where this pro-apoptotic complex acts not established
   • Whether CDIP1 binding requires filament assembly unknown
9. 2021 Medium

   Extended VPS37B function to immune endocytosis, showing it enables mannose-receptor-mediated allergen uptake in dendritic cells and shapes Th2 responses.

   Evidence CRISPR/Cas9 knockout, RNA-seq, T-cell co-culture cytokine assays, and an in vivo mouse allergic rhinitis model

   PMID:33895493

   Open questions at the time

   • Direct interaction of VPS37B with the mannose receptor pathway not demonstrated
   • VPS37B-specific vs VPS37A contribution not fully separated

• How VPS37B isoform identity selects distinct cargo and effector outcomes (EGFR sorting, ALIX/CDIP1 apoptosis, allergen endocytosis) versus the redundant budding role remains unresolved.
• No structural map of VPS37B-specific binding surfaces for SH3YL1, ALG-2, or CDIP1
• Mechanism coupling ESCRT-I destabilization to p21/NF-κB signaling unknown
• In vivo physiological requirement for VPS37B in mammalian tissues not defined