SAMHD1 phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity.
SAMHD1 phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity.
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DOI：
10.1371/journal.ppat.1008855
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发表时间：
2020-09
期刊：
影响因子：
6.7
通讯作者：
Cerboni C
中科院分区：
文献类型：
--
作者：
De Meo S;Dell'Oste V;Molfetta R;Tassinari V;Lotti LV;Vespa S;Pignoloni B;Covino DA;Fantuzzi L;Bona R;Zingoni A;Nardone I;Biolatti M;Coscia A;Paolini R;Benkirane M;Edfors F;Sandalova T;Achour A;Hiscott J;Landolfo S;Santoni A;Cerboni C
SAMHD1是一种宿主限制因子，其功能是限制逆转录病毒和DNA病毒，基于其核脱氧核苷酸三磷酸（dNTP）水解酶活性，限制细胞内dNTP池的可用性。在本研究中，我们证明了SAMHD1在人巨细胞病毒（HCMV）感染后表达增加，但对感染性病毒的产生只有适度的影响。SAMHD1在感染后被细胞周期蛋白依赖性激酶（尤其是Cdk2）和病毒激酶pUL97在残基T592处迅速磷酸化，导致很大一部分phoho -SAMHD1重新定位到感染成纤维细胞的细胞质中，与病毒颗粒和致密体相关。因此，我们的研究结果表明，HCMV依赖的SAMHD1细胞质脱位和失活可能是HCMV逃避宿主抗病毒限制活性的潜在新机制。人类巨细胞病毒（HCMV）是世界范围内传播最广泛的病毒之一，在没有完全免疫系统的个体（例如移植患者和婴儿）中引起严重的全身性疾病。因此，宿主免疫反应对于控制HCMV在整个机体中的复制和传播至关重要。一些属于先天免疫系统的一线蛋白，被称为限制性因子，甚至在病原体感染细胞之前就已经表达和活跃，并且能够介导细胞对感染的内在抵抗。其中包括SAMHD1，一种核脱氧核苷酸三磷酸（dNTP）水解酶，它限制细胞内dNTP的可用性，dNTP是生长DNA分子（包括复制病毒的DNA分子）的必要成分。因此，我们研究了SAMHD1抵抗HCMV感染的能力。我们发现SAMHD1的表达在感染后上调，但在限制病毒复制方面只有适度的作用。这主要是由于hcmv诱导的苏氨酸-592（已知负调节病毒限制的关键残基）磷酸化，phosphoT592-SAMHD1重新定位到感染细胞的细胞质，以及它与病毒颗粒的关联。这一前所未有的发现可能会影响SAMHD1在HCMV感染时的功能，因此可能代表了一种新的HCMV介导的免疫逃避策略，需要进一步的研究。
SAMHD1 is a host restriction factor that functions to restrict both retroviruses and DNA viruses, based on its nuclear deoxynucleotide triphosphate (dNTP) hydrolase activity that limits availability of intracellular dNTP pools. In the present study, we demonstrate that SAMHD1 expression was increased following human cytomegalovirus (HCMV) infection, with only a modest effect on infectious virus production. SAMHD1 was rapidly phosphorylated at residue T592 after infection by cellular cyclin-dependent kinases, especially Cdk2, and by the viral kinase pUL97, resulting in a significant fraction of phosho-SAMHD1 being relocalized to the cytoplasm of infected fibroblasts, in association with viral particles and dense bodies. Thus, our findings indicate that HCMV-dependent SAMHD1 cytoplasmic delocalization and inactivation may represent a potential novel mechanism of HCMV evasion from host antiviral restriction activities. Human cytomegalovirus (HCMV) is among the most widespread viruses worldwide, causing severe systemic illness in individuals without a fully competent immune system (e.g., transplanted patients and infants). Therefore, host immune response is crucial to control HCMV replication and dissemination throughout the organism. Some frontline proteins belonging to the innate immune system, known as restriction factors, are already expressed and active even before a pathogen infects a cell and are able to mediate a cell-intrinsic resistance to infections. Among them is SAMHD1, a nuclear deoxynucleotide triphosphate (dNTP) hydrolase that limits the availability of intracellular dNTPs, essential components of growing DNA molecules, including those of replicating viruses. We thus investigated SAMHD1 ability to counteract HCMV infection. We show that SAMHD1 expression was upregulated after infection, but with only a modest effect in limiting viral replication. This was mainly due to HCMV-induced phosphorylation at Threonine-592 (the key residue known to negatively regulate viral restriction), to phosphoT592-SAMHD1 relocalization to the cytoplasm of infected cells, and to its association with viral particles. The unprecedented observation of relocation of phosphoT592-SAMHD1 outside the nucleus may affect SAMHD1 function upon HCMV infection, and thus might represent a novel HCMV-mediated immune evasion strategy that will need further investigations.
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