HIV-1 Nef interacts with the cyclin K/CDK13 complex to antagonize SERINC5 for optimal viral infectivity
Qingqing Chai,
Sunan Li,
Morgan K. Collins,
Rongrong Li,
Iqbal Ahmad,
Silas F. Johnson,
Dylan A. Frabutt,
Zhichang Yang,
Xiaojing Shen,
Liangliang Sun,
Jian Hu,
Judd F. Hultquist,
B. Matija Peterlin,
Yong-Hui Zheng
Affiliations
Qingqing Chai
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
Sunan Li
Harbin Veterinary Research Institute, CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences, Harbin, China
Morgan K. Collins
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
Rongrong Li
Harbin Veterinary Research Institute, CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences, Harbin, China
Iqbal Ahmad
Harbin Veterinary Research Institute, CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences, Harbin, China
Silas F. Johnson
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA; Department of Biology, Hillsdale College, Hillsdale, MI, USA
Dylan A. Frabutt
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
Zhichang Yang
Department of Chemistry, Michigan State University, East Lansing, MI, USA
Xiaojing Shen
Department of Chemistry, Michigan State University, East Lansing, MI, USA
Liangliang Sun
Department of Chemistry, Michigan State University, East Lansing, MI, USA
Jian Hu
Department of Chemistry, Michigan State University, East Lansing, MI, USA; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
Judd F. Hultquist
Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
B. Matija Peterlin
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA
Yong-Hui Zheng
Harbin Veterinary Research Institute, CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences, Harbin, China; Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA; Corresponding author
Summary: HIV-1-negative factor (Nef) protein antagonizes serine incorporator 5 (SERINC5) by redirecting this potent restriction factor to the endosomes and lysosomes for degradation. However, the precise mechanism remains unclear. Using affinity purification/mass spectrometry, we identify cyclin K (CycK) and cyclin-dependent kinase 13 (CDK13) as a Nef-associated kinase complex. CycK/CDK13 phosphorylates the serine at position 360 (S360) in SERINC5, which is required for Nef downregulation of SERINC5 from the cell surface and its counteractivity of the SERINC5 antiviral activity. To understand the role of S360 phosphorylation, we generate chimeric proteins between CD8 and SERINC5 to study their response to Nef. Nef not only downregulates but, importantly, also binds to this chimera in an S360-dependent manner. Thus, S360 phosphorylation increases interactions between Nef and SERINC5 and initiates the destruction of SERINC5 by the endocytic machinery.
