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PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation

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 p...

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Autores principales: Miyakawa, Kei, Matsunaga, Satoko, Yokoyama, Masaru, Nomaguchi, Masako, Kimura, Yayoi, Nishi, Mayuko, Kimura, Hirokazu, Sato, Hironori, Hirano, Hisashi, Tamura, Tomohiko, Akari, Hirofumi, Miura, Tomoyuki, Adachi, Akio, Sawasaki, Tatsuya, Yamamoto, Naoki, Ryo, Akihide
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479052/
https://www.ncbi.nlm.nih.gov/pubmed/31015445
http://dx.doi.org/10.1038/s41467-019-09867-7
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author Miyakawa, Kei
Matsunaga, Satoko
Yokoyama, Masaru
Nomaguchi, Masako
Kimura, Yayoi
Nishi, Mayuko
Kimura, Hirokazu
Sato, Hironori
Hirano, Hisashi
Tamura, Tomohiko
Akari, Hirofumi
Miura, Tomoyuki
Adachi, Akio
Sawasaki, Tatsuya
Yamamoto, Naoki
Ryo, Akihide
author_facet Miyakawa, Kei
Matsunaga, Satoko
Yokoyama, Masaru
Nomaguchi, Masako
Kimura, Yayoi
Nishi, Mayuko
Kimura, Hirokazu
Sato, Hironori
Hirano, Hisashi
Tamura, Tomohiko
Akari, Hirofumi
Miura, Tomoyuki
Adachi, Akio
Sawasaki, Tatsuya
Yamamoto, Naoki
Ryo, Akihide
author_sort Miyakawa, Kei
collection PubMed
description 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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spelling pubmed-64790522019-04-25 PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation Miyakawa, Kei Matsunaga, Satoko Yokoyama, Masaru Nomaguchi, Masako Kimura, Yayoi Nishi, Mayuko Kimura, Hirokazu Sato, Hironori Hirano, Hisashi Tamura, Tomohiko Akari, Hirofumi Miura, Tomoyuki Adachi, Akio Sawasaki, Tatsuya Yamamoto, Naoki Ryo, Akihide Nat Commun Article 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. Nature Publishing Group UK 2019-04-23 /pmc/articles/PMC6479052/ /pubmed/31015445 http://dx.doi.org/10.1038/s41467-019-09867-7 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Miyakawa, Kei
Matsunaga, Satoko
Yokoyama, Masaru
Nomaguchi, Masako
Kimura, Yayoi
Nishi, Mayuko
Kimura, Hirokazu
Sato, Hironori
Hirano, Hisashi
Tamura, Tomohiko
Akari, Hirofumi
Miura, Tomoyuki
Adachi, Akio
Sawasaki, Tatsuya
Yamamoto, Naoki
Ryo, Akihide
PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation
title PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation
title_full PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation
title_fullStr PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation
title_full_unstemmed PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation
title_short PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation
title_sort pim kinases facilitate lentiviral evasion from samhd1 restriction via vpx phosphorylation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479052/
https://www.ncbi.nlm.nih.gov/pubmed/31015445
http://dx.doi.org/10.1038/s41467-019-09867-7
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