PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation

Kei Miyakawa, Satoko Matsunaga, Masaru Yokoyama, Masako Nomaguchi, Yayoi Kimura, Mayuko Nishi, Hirokazu Kimura, Hironori Sato, Hisashi Hirano, Tomohiko Tamura, Hirofumi Akari, Tomoyuki Miura, Akio Adachi, Tatsuya Sawasaki, Naoki Yamamoto and Akihide Ryo ()
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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
Tomoyuki Miura: Kyoto University
Akio Adachi: Tokushima University Graduate School of Medical Science
Tatsuya Sawasaki: Ehime University
Naoki Yamamoto: National Institute of Infectious Diseases
Akihide Ryo: Yokohama City University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09867-7

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