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PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation

Author

Listed:
  • Kei Miyakawa

    (Yokohama City University School of Medicine)

  • Satoko Matsunaga

    (Yokohama City University School of Medicine)

  • Masaru Yokoyama

    (National Institute of Infectious Diseases)

  • Masako Nomaguchi

    (Tokushima University Graduate School of Medical Science)

  • Yayoi Kimura

    (Yokohama City University)

  • Mayuko Nishi

    (Yokohama City University School of Medicine)

  • Hirokazu Kimura

    (Gunma Paz University)

  • Hironori Sato

    (National Institute of Infectious Diseases)

  • Hisashi Hirano

    (Yokohama City University)

  • Tomohiko Tamura

    (Yokohama City University School of Medicine)

  • Hirofumi Akari

    (Kyoto University
    Kyoto University)

  • Tomoyuki Miura

    (Kyoto University)

  • Akio Adachi

    (Tokushima University Graduate School of Medical Science
    Kansai Medical University)

  • Tatsuya Sawasaki

    (Ehime University)

  • Naoki Yamamoto

    (National Institute of Infectious Diseases
    Tokyo Medical and Dental University)

  • Akihide Ryo

    (Yokohama City University School of Medicine
    Yokohama City University)

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.

Suggested Citation

  • Kei Miyakawa & Satoko Matsunaga & Masaru Yokoyama & Masako Nomaguchi & Yayoi Kimura & Mayuko Nishi & Hirokazu Kimura & Hironori Sato & Hisashi Hirano & Tomohiko Tamura & Hirofumi Akari & Tomoyuki Miur, 2019. "PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09867-7
    DOI: 10.1038/s41467-019-09867-7
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