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SNARE mimicry by the CD225 domain of IFITM3 enables regulation of homotypic late endosome fusion
Open accessPreprint — published as 10.1038/s44318-024-00334-8
Abstract
The CD225/Dispanins superfamily consists of membrane proteins that regulate vesicular transport and membrane fusion events driving neurotransmission, glucose transport, and antiviral immunity. However, how the CD225 domain controls membrane trafficking was unknown. We reveal that the CD225 domain contains a SNARE-like motif that enables interaction with cellular SNARE fusogens. Proline rich transmembrane protein 2 (PRRT2) encodes a SNARE-like motif that enables interaction with neuronal SNARE proteins, and mutations therein disrupt SNARE binding and are linked to neurological disease. Another CD225 member, interferon-induced transmembrane protein 3 (IFITM3), protects cells against Influenza A virus infection. IFITM3 interacts with SNARE proteins that mediate late endosome-late endosome (homotypic) fusion and late endosome-lysosome (heterotypic) fusion. IFITM3 binds to syntaxin 7 (STX7) in cells and in vitro, and mutations that abrogate STX7 binding cause loss of antiviral activity against Influenza A virus. Mechanistically, IFITM3 disrupts assembly of the SNARE complex controlling homotypic fusion and accelerates the trafficking of endosomal cargo to lysosomes. Our results suggest that SNARE modulation plays a previously unrecognized role in the diverse functions performed by CD225 proteins.
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Metadata
- Authors
- Rahman, K., Wilt, I., Jolley, A. A., Chowdhury, B., Datta, S. A. K., & Compton, A. A.
- Affiliations
- North South University (BD)
- National Cancer Institute (US)
- Corresponding author
- Compton, Alex A.
- Venue
- The EMBO Journal
- Publisher
- openRxiv
- Published
- 2024-08-08
- Volume
- 44
- Issue
- 2
- Pages
- 534-562
- ISSN
- 0261-4189 (ISSN-L)
- PMC
- PMC11730294
- OpenAlex
- W4405187573
- Cited by
- 12
- References
- 89
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 1
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, public-domain)
- PubMed Central (publishedVersion, cc-by)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion, public-domain)
- Funders
- National Institutes of Health
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- IFITM3, SNARE complex assembly, homotypic membrane fusion, syntaxin 7, PRRT2, antiviral immunity, endosomal trafficking, lysosomes, membrane trafficking
- MeSH terms
- Protein Domains, Animals, Humans, Lysosomes, Membrane Fusion, Membrane Proteins, Influenza A virus, Protein Binding, Endosomes, RNA-Binding Proteins, SNARE Proteins, Qa-SNARE Proteins, HEK293 Cells
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