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IFITM3的CD225结构域通过SNARE模拟实现对同型晚期内体融合的调控。

SNARE mimicry by the CD225 domain of IFITM3 enables regulation of homotypic late endosome fusion.

作者信息

Rahman Kazi, Wilt Isaiah, Jolley Abigail A, Chowdhury Bhabadeb, Datta Siddhartha A K, Compton Alex A

机构信息

HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.

Department of Biochemistry and Microbiology, School of Health and Life Sciences, North South University, Dhaka, Bangladesh.

出版信息

EMBO J. 2025 Jan;44(2):534-562. doi: 10.1038/s44318-024-00334-8. Epub 2024 Dec 9.

DOI:10.1038/s44318-024-00334-8
PMID:39653855
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11730294/
Abstract

The CD225/Dispanin superfamily contains membrane proteins that regulate vesicular transport and membrane fusion events required for neurotransmission, glucose transport, and antiviral immunity. However, how the CD225 domain controls membrane trafficking has remained unknown. Here we show 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; mutations in this region 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.

摘要

CD225/Dispanin超家族包含调节神经传递、葡萄糖转运和抗病毒免疫所需的囊泡运输和膜融合事件的膜蛋白。然而，CD225结构域如何控制膜运输仍不清楚。在这里，我们表明CD225结构域包含一个类似SNARE的基序，能够与细胞SNARE融合蛋白相互作用。富含脯氨酸的跨膜蛋白2（PRRT2）编码一个类似SNARE的基序，能够与神经元SNARE蛋白相互作用；该区域的突变会破坏SNARE结合，并与神经疾病有关。另一个CD225成员，干扰素诱导跨膜蛋白3（IFITM3），可保护细胞免受甲型流感病毒感染。IFITM3与介导晚期内体-晚期内体（同型）融合和晚期内体-溶酶体（异型）融合的SNARE蛋白相互作用。IFITM3在细胞内和体外均与 syntaxin 7（STX7）结合，消除STX7结合的突变会导致对甲型流感病毒的抗病毒活性丧失。从机制上讲，IFITM3破坏了控制同型融合的SNARE复合体的组装，并加速了内体货物向溶酶体的运输。我们的结果表明，SNARE调节在CD225蛋白执行的多种功能中发挥了以前未被认识到的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/844d/11730294/3ee97dcf2329/44318_2024_334_Fig13_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/844d/11730294/634191d8abc4/44318_2024_334_Fig5_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/844d/11730294/54bce3e85b91/44318_2024_334_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/844d/11730294/e62c773866b6/44318_2024_334_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/844d/11730294/ee78a6783da7/44318_2024_334_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/844d/11730294/3c97d4205767/44318_2024_334_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/844d/11730294/83e0a66642f9/44318_2024_334_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/844d/11730294/340899c7be45/44318_2024_334_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/844d/11730294/3ee97dcf2329/44318_2024_334_Fig13_ESM.jpg

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