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Cul3-KLHL20 E3 ubiquitin ligase plays a key role in the arms race between HIV-1 Nef and host SERINC5 restriction

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  • Sunan Li

    (CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences)

  • Rongrong Li

    (CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences)

  • Iqbal Ahmad

    (CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences)

  • Xiaomeng Liu

    (CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences)

  • Silas F. Johnson

    (Michigan State University)

  • Liangliang Sun

    (Michigan State University)

  • Yong-Hui Zheng

    (CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences
    Michigan State University)

Abstract

HIV-1 must counteract various host restrictions to establish productive infection. SERINC5 is a potent restriction factor that blocks HIV-1 entry from virions, but its activity is counteracted by Nef. The SERINC5 and Nef activities are both initiated from the plasma membrane, where SERINC5 is packaged into virions for viral inhibition or downregulated by Nef via lysosomal degradation. However, it is still unclear how SERINC5 is localized to and how its expression is regulated on the plasma membrane. We now report that Cullin 3-KLHL20, a trans-Golgi network (TGN)-localized E3 ubiquitin ligase, polyubiquitinates SERINC5 at lysine 130 via K33/K48-linked ubiquitination. The K33-linked polyubiquitination determines SERINC5 expression on the plasma membrane, and the K48-linked polyubiquitination contributes to SERINC5 downregulation from the cell surface. Our study reveals an important role of K130 polyubiquitination and K33/K48-linked ubiquitin chains in HIV-1 infection by regulating SERINC5 post-Golgi trafficking and degradation.

Suggested Citation

  • Sunan Li & Rongrong Li & Iqbal Ahmad & Xiaomeng Liu & Silas F. Johnson & Liangliang Sun & Yong-Hui Zheng, 2022. "Cul3-KLHL20 E3 ubiquitin ligase plays a key role in the arms race between HIV-1 Nef and host SERINC5 restriction," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30026-y
    DOI: 10.1038/s41467-022-30026-y
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    References listed on IDEAS

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    1. Chao Liu & Weixiao Liu & Yihong Ye & Wei Li, 2017. "Ufd2p synthesizes branched ubiquitin chains to promote the degradation of substrates modified with atypical chains," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
    2. Yoshiko Usami & Yuanfei Wu & Heinrich G. Göttlinger, 2015. "SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef," Nature, Nature, vol. 526(7572), pages 218-223, October.
    3. Annachiara Rosa & Ajit Chande & Serena Ziglio & Veronica De Sanctis & Roberto Bertorelli & Shih Lin Goh & Sean M. McCauley & Anetta Nowosielska & Stylianos E. Antonarakis & Jeremy Luban & Federico And, 2015. "HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation," Nature, Nature, vol. 526(7572), pages 212-217, October.
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