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Cited by 11Cellular transport and secretionExtracellular vesicles in diseaseAutophagy in Disease and Therapy

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VARP binds SNX27 to promote endosomal supercomplex formation on membranes

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Chandra, Mintu, Kendall, Amy K., Ford, Marijn G. J., Jackson, Lauren P.·2025·Science Advances
DOI 10.1126/sciadv.adr9340PMC PMC11817943

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Abstract

Endosomes are vital cellular hubs for sorting protein cargoes. Retromer (VPS26/VPS35/VPS29) binds multiple sorting nexin (SNX) proteins on endosomal membranes, but assembly mechanisms of metazoan SNX/Retromer complexes remain elusive. We combine biochemical and biophysical approaches with AlphaFold modeling to identify a previously unidentified direct interaction between SNX27 and VARP. A full biochemical reconstitution system using purified proteins systematically tests how and when coats are recruited to membranes to generate tubules. We demonstrate and measure how specific combinations of Retromer with SNX27, ESCPE-1 (SNX2/SNX6), or both complexes, remodel membranes containing physiological cargo and phospholipids. SNX27, alone and with Retromer, remodels membranes with PI(3)P and PDZbm cargo. ESCPE-1 deforms membranes with bis-phosphoinositides and CI-MPR cargo but surprisingly does not recruit Retromer. VARP co-immunoprecipitates all coat components in cells and is required to reconstitute a proposed endosomal “supercomplex” (SNX27, ESCPE-1, and Retromer) in vitro. These data suggest VARP regulates metazoan endosomal coat assembly to promote cargo sorting out of endosomes.

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Metadata

Authors
Chandra, M., Kendall, A. K., Ford, M. G. J., & Jackson, L. P.
Affiliations
  • Vanderbilt University (US)
  • University of Pittsburgh (US)
Corresponding author
Jackson, Lauren P.
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2025-02-14
Volume
11
Issue
7
Pages
eadr9340-eadr9340
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.adr9340
PMC
PMC11817943
OpenAlex
W4407394537
Cited by
11
References
2
Citations by year
2026: 6 · 2025: 5
FWCI
5.46
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • Vanderbilt University
  • National Institutes of Health (1s10od030292-01)
  • National Institute of General Medical Sciences (R35GM139546, R35GM119525)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords
SNX27, retromer, sorting nexins, membrane remodeling, protein sorting, phosphatidylinositol 3-phosphate, cargo sorting, endosomes

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