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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish (US)
Article number109514
JournalCell reports
Issue number6
StatePublished - Aug 10 2021


  • AP-2
  • CDK
  • HIV-1
  • Nef
  • cyclin
  • endocytosis
  • intrinsic immunity
  • restriction factors
  • serine phosphorylation

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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