SUMOylation Promotes PML Degradation during Encephalomyocarditis Virus Infection
SUMOylation Promotes PML Degradation during Encephalomyocarditis Virus Infection
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DOI：
10.1128/jvi.01321-10
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发表时间：
2010-11-01
影响因子：
5.4
通讯作者：
Chelbi-Alix, Mounira K.
中科院分区：
文献类型：
--
作者：
El Mchichi, Bouchra;Regad, Tarik;Chelbi-Alix, Mounira K.
早幼粒细胞白血病 (PML) 蛋白在核质的弥漫核部分和基质相关结构（称为核体 (NB)）中表达。 PML NB 的形成需要 PML 共价修饰为 SUMO。基于 PML 内 SUMO 相互作用基序的鉴定，SUMO 与 PML 的非共价相互作用似乎是在 PML NB 内进一步招募 SUMO 化蛋白所必需的。 RNA病毒的复制发生在细胞质中并被PML抑制，它们已经开发出各种策略来抵消PML NB介导的抗病毒防御。我们在此表明，来自 PML 敲除小鼠的原代成纤维细胞对脑心肌炎病毒 (EMCV) 感染更敏感，这表明 PML 的缺失会导致 EMCV 复制的增加。此外，我们发现 EMCV 会导致干扰素处理的细胞和表达 PMLIII 的细胞中 PML 蛋白水平降低。 PML 的还原是通过 EMCV 3C 蛋白酶进行的。事实上，在感染后早期，EMCV 诱导 PML 从核质转移到核基质，并诱导 PML 与 SUMO-1、SUMO-2 和 SUMO-3 结合，导致 PML 体大小增加，其中病毒蛋白酶 3C 和蛋白酶体成分被发现与 PML 共定位于 NB 内。该过程之后是 PML 降解，以蛋白酶体和 SUMO 依赖性方式发生，并且不涉及 PML 的 SUMO 相互作用基序。总之，这些发现揭示了 EMCV 进化出的一种新机制，可以在干扰素诱导的抗病毒防御中拮抗 PML 途径。
The promyelocytic leukemia (PML) protein is expressed in the diffuse nuclear fraction of the nucleoplasm and in matrix-associated structures, known as nuclear bodies (NBs). PML NB formation requires the covalent modification of PML to SUMO. The noncovalent interactions of SUMO with PML based on the identification of a SUMO-interacting motif within PML seem to be required for further recruitment within PML NBs of SUMOylated proteins. RNA viruses whose replication takes place in the cytoplasm and is inhibited by PML have developed various strategies to counteract the antiviral defense mediated by PML NBs. We show here that primary fibroblasts derived from PML knockout mice are more sensitive to infection with encephalomyocarditis virus (EMCV), suggesting that the absence of PML results in an increase in EMCV replication. Also, we found that EMCV induces a decrease in PML protein levels both in interferon-treated cells and in PMLIII-expressing cells. Reduction of PML was carried out by the EMCV 3C protease. Indeed, at early times postinfection, EMCV induced PML transfer from the nucleoplasm to the nuclear matrix and PML conjugation to SUMO-1, SUMO-2, and SUMO-3, leading to an increase in PML body size where the viral protease 3C and the proteasome component were found colocalizing with PML within the NBs. This process was followed by PML degradation occurring in a proteasome-and SUMO-dependent manner and did not involve the SUMO-interacting motif of PML. Together, these findings reveal a new mechanism evolved by EMCV to antagonize the PML pathway in the interferon-induced antiviral defense.