PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation
PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation
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DOI：
10.1038/s41467-019-09867-7
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发表时间：
2019-04-23
影响因子：
16.6
通讯作者：
Ryo, Akihide
中科院分区：
文献类型：
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作者：
Miyakawa, Kei;Matsunaga, Satoko;Ryo, Akihide
慢病毒已经进化为获得辅助蛋白Vpx以抵消内在宿主限制因子SAMHD 1。虽然Vpx是磷酸化的，但仍不清楚这种磷酸化是否真的调节其对SAMHD 1的活性。在这里，我们确定的PIM家庭的丝氨酸/苏氨酸蛋白激酶的因素负责Vpx的磷酸化和促进Vpx介导的SAMHD 1的抵消。整合蛋白质组学和随后的功能分析表明，PIM家族激酶，PIM 1和PIM 3，磷酸化HIV-2 Vpx在Ser 13和稳定Vpx与SAMHD 1的相互作用，从而促进泛素介导的SAMHD 1的蛋白水解。PIM激酶的抑制促进SAMHD 1的抗病毒活性，最终减少病毒复制。我们的研究结果强调了一种新的病毒-宿主细胞相互作用模式，其中宿主PIM激酶通过抵消宿主抗病毒系统促进病毒感染性，并提出了一种新的治疗策略，涉及恢复SAMHD 1介导的抗病毒反应。
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.