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TRIM21-mediated proteasomal degradation of SAMHD1 regulates its antiviral activity.
EMBO Reports ( IF 6.5 ) Pub Date : 2019-12-04 , DOI: 10.15252/embr.201847528
Zhaolong Li 1 , Chen Huan 1 , Hong Wang 1 , Yue Liu 1 , Xin Liu 1 , Xing Su 1 , Jinghua Yu 1 , Zhilei Zhao 1 , Xiao-Fang Yu 1, 2 , Baisong Zheng 1 , Wenyan Zhang 1
Affiliation  

SAMHD1 possesses multiple functions, but whether cellular factors regulate SAMHD1 expression or its function remains not well characterized. Here, by investigating why cultured RD and HEK293T cells show different sensitivity to enterovirus 71 (EV71) infection, we demonstrate that SAMHD1 is a restriction factor for EV71. Importantly, we identify TRIM21, an E3 ubiquitin ligase, as a key regulator of SAMHD1, which specifically interacts and degrades SAMHD1 through the proteasomal pathway. However, TRIM21 has no effect on EV71 replication itself. Moreover, we prove that interferon production stimulated by EV71 infection induces increased TRIM21 and SAMHD1 expression, whereas increasing TRIM21 overrides SAMHD1 inhibition of EV71 in cells and in a neonatal mouse model. TRIM21-mediated degradation of SAMHD1 also affects SAMHD1-dependent restriction of HIV-1 and the regulation of interferon production. We further identify the functional domains in TRIM21 required for SAMHD1 binding and the ubiquitination site K622 in SAMHD1 and show that phosphorylation of SAMHD1 at T592 also blocks EV71 restriction. Our findings illuminate how EV71 overcomes SAMHD1 inhibition via the upregulation of TRIM21.

中文翻译:


TRIM21 介导的 SAMHD1 蛋白酶体降解可调节其抗病毒活性。



SAMHD1具有多种功能,但细胞因子是否调节SAMHD1表达或其功能仍不清楚。在这里,通过研究为什么培养的 RD 和 HEK293T 细胞对肠道病毒 71 (EV71) 感染表现出不同的敏感性,我们证明 SAMHD1 是 EV71 的限制因子。重要的是,我们确定 TRIM21(一种 E3 泛素连接酶)是 SAMHD1 的关键调节因子,它通过蛋白酶体途径特异性相互作用并降解 SAMHD1。然而,TRIM21 对 EV71 复制本身没有影响。此外,我们证明,EV71感染刺激的干扰素产生会诱导TRIM21和SAMHD1表达增加,而在细胞和新生小鼠模型中,TRIM21的增加会覆盖EV71的SAMHD1抑制。 TRIM21 介导的 SAMHD1 降解也会影响 SAMHD1 依赖性的 HIV-1 限制和干扰素产生的调节。我们进一步鉴定了 SAMHD1 结合所需的 TRIM21 功能域和 SAMHD1 中的泛素化位点 K622,并表明 SAMHD1 在 T592 处的磷酸化也可阻断 EV71 限制。我们的研究结果阐明了 EV71 如何通过上调 TRIM21 克服 SAMHD1 抑制。
更新日期:2020-01-07
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