2. Academic Validation
  3. PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation

PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation

  • Nat Commun. 2019 Apr 23;10(1):1844. doi: 10.1038/s41467-019-09867-7.
Kei Miyakawa 1,  Satoko Matsunaga 1,  Masaru Yokoyama 2,  Masako Nomaguchi 3,  Yayoi Kimura 4,  Mayuko Nishi 1,  Hirokazu Kimura 5,  Hironori Sato 2,  Hisashi Hirano 4,  Tomohiko Tamura 6,  Hirofumi Akari 7 8,  Tomoyuki Miura 8,  Akio Adachi 3 9,  Tatsuya Sawasaki 10,  Naoki Yamamoto 11 12,  Akihide Ryo 13 14
Affiliations

Affiliations

  • 1 Department of Microbiology, Yokohama City University School of Medicine, Kanagawa, 236-0004, Japan.
  • 2 Pathogen Genomics Center, National Institute of Infectious Diseases, Musashi Murayama, Tokyo, 208-0011, Japan.
  • 3 Department of Microbiology, Tokushima University Graduate School of Medical Science, Tokushima, 770-8503, Japan.
  • 4 Advanced Medical Research Center, Yokohama City University, Kanagawa, 236-0004, Japan.
  • 5 School of Medical Technology, Faculty of Health Sciences, Gunma Paz University, Gunma, 370-0006, Japan.
  • 6 Department of Immunology, Yokohama City University School of Medicine, Kanagawa, 236-0004, Japan.
  • 7 Laboratory of Infectious Disease Model, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.
  • 8 Center for Human Evolution Modeling Research, Primate Research Institute, Kyoto University, Aichi, 484-8506, Japan.
  • 9 Department of Microbiology, Kansai Medical University, Osaka, 573-1010, Japan.
  • 10 Proteo-Science Center, Ehime University, Ehime, 790-8577, Japan.
  • 11 National Institute of Infectious Diseases, Tokyo, 162-8640, Japan.
  • 12 Tokyo Medical and Dental University, Tokyo, 113-8519, Japan.
  • 13 Department of Microbiology, Yokohama City University School of Medicine, Kanagawa, 236-0004, Japan. aryo@yokohama-cu.ac.jp.
  • 14 Advanced Medical Research Center, Yokohama City University, Kanagawa, 236-0004, Japan. aryo@yokohama-cu.ac.jp.
PMID: 31015445 DOI: 10.1038/s41467-019-09867-7
Abstract

Lentiviruses have evolved to acquire an auxiliary protein Vpx to counteract the intrinsic host restriction factor SAMHD1. Although Vpx is phosphorylated, it remains unclear whether such phosphorylation indeed regulates its activity toward SAMHD1. Here we identify the Pim family of serine/threonine protein kinases as the factors responsible for the phosphorylation of Vpx and the promotion of Vpx-mediated SAMHD1 counteraction. Integrated proteomics and subsequent functional analysis reveal that Pim family kinases, PIM1 and PIM3, phosphorylate HIV-2 Vpx at Ser13 and stabilize the interaction of Vpx with SAMHD1 thereby promoting ubiquitin-mediated proteolysis of SAMHD1. Inhibition of the Pim kinases promotes the Antiviral activity of SAMHD1, ultimately reducing viral replication. Our results highlight a new mode of virus-host cell interaction in which host Pim kinases facilitate promotion of viral infectivity by counteracting the host Antiviral system, and suggest a novel therapeutic strategy involving restoration of SAMHD1-mediated Antiviral response.

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