Chromatin-Remodeling Factor SPOC1 Acts as a Cellular Restriction Factor against Human Cytomegalovirus by Repressing the Major Immediate Early Promoter
Chromatin-Remodeling Factor SPOC1 Acts as a Cellular Restriction Factor against Human Cytomegalovirus by Repressing the Major Immediate Early Promoter
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染色质重塑因子 SPOC1 通过抑制主要立即早期启动子作为抗人巨细胞病毒的细胞限制因子
DOI：
10.1128/jvi.00342-18
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发表时间：
2018
影响因子：
5.4
通讯作者：
Stamminger T
中科院分区：
文献类型：
--
作者：
Reichel A;Stilp AC;Scherer M;Reuter N;Lukassen S;Kasmapour B;Schreiner S;Cicin-Sain L;Winterpacht A;Stamminger T
细胞蛋白 SPOC1（卵巢癌中与生存时间相关的 PHD [植物同源域]指蛋白 1）充当染色质结构和 DNA 损伤反应的调节剂。它结合含有 H3K4me2/3 的染色质，并通过招募 KAP-1 和 H3K9 甲基转移酶等辅阻遏物来促进 DNA 浓缩。先前的研究发现 SPOC1 是人类腺病毒 (HAdV) 感染的限制因子，可通过 E1B-55K/E4-orf6 依赖性蛋白酶体降解来拮抗。在这里，我们证明，与 HAdV 感染的细胞相比，SPOC1 在人巨细胞病毒 (HCMV) 复制的早期阶段短暂上调。我们证明立即早期蛋白 1 (IE1) 的表达对于诱导 SPOC1 是充分且必要的。此外，我们发现在感染后期，SPOC1 以糖原合酶激酶 3β (GSK-3β) 依赖性方式下调。我们提供的证据表明，SPOC1 过度表达通过抑制病毒立即早期 (IE) 基因表达的启动，严重损害 HCMV 复制。我们一致地观察到 SPOC1 缺失的原代人成纤维细胞表现出病毒 IE 基因表达的增强。这种情况以感染复数 (MOI) 依赖性方式发生，这是内在免疫的一个明确标志。有趣的是，抑制需要在感染开始时 SPOC1 水平较高，而随后的上调没有负面影响，这表明 SPOC1 在 HCMV 复制周期中具有不同的时间作用。从机制上讲，我们观察到 SPOC1 与主要立即早期启动子 (MIEP) 的高度特异性关联，强烈表明 SPOC1 通过 MIEP 结合和随后的异染色质构建因子的招募来抑制 HCMV 复制。因此，我们的数据将 SPOC1 作为一种新因子添加到宿主细胞的天赋中，以限制巨细胞病毒感染。重要性越来越多的证据表明，在数千年的共同进化过程中，宿主细胞已经开发出复杂的细胞因子汇编来限制巨细胞病毒感染。定义这种设备对于了解针对病毒感染的细胞屏障并制定利用这些因素进行抗病毒方法的策略非常重要。迄今为止，已知 PML 核体和干扰素 γ 诱导蛋白 16 (IFI16) 的成分可介导针对 HCMV 的内在免疫。在这项研究中，我们将染色质调节剂 SPOC1 确定为针对 HCMV 的新型限制因子。我们发现，预先存在的高 SPOC1 蛋白水平通过与重要的病毒顺式调节元件（主要的立即早期启动子）的特定关联介导 HCMV 基因表达的沉默。由于 SPOC1 表达因细胞类型而异，因此该因子可能在针对 HCMV 的组织特异性防御中发挥重要作用。
The cellular protein SPOC1 (survival time-associated PHD [plant homeodomain] finger protein in ovarian cancer 1) acts as a regulator of chromatin structure and the DNA damage response. It binds H3K4me2/3-containing chromatin and promotes DNA condensation by recruiting corepressors such as KAP-1 and H3K9 methyltransferases. Previous studies identified SPOC1 as a restriction factor against human adenovirus (HAdV) infection that is antagonized by E1B-55K/E4-orf6-dependent proteasomal degradation. Here, we demonstrate that, in contrast to HAdV-infected cells, SPOC1 is transiently upregulated during the early phase of human cytomegalovirus (HCMV) replication. We show that the expression of immediate early protein 1 (IE1) is sufficient and necessary to induce SPOC1. Additionally, we discovered that during later stages of infection, SPOC1 is downregulated in a glycogen synthase kinase 3β (GSK-3β)-dependent manner. We provide evidence that SPOC1 overexpression severely impairs HCMV replication by repressing the initiation of viral immediate early (IE) gene expression. Consistently, we observed that SPOC1-depleted primary human fibroblasts displayed an augmented initiation of viral IE gene expression. This occurs in a multiplicity of infection (MOI)-dependent manner, a defining hallmark of intrinsic immunity. Interestingly, repression requires the presence of high SPOC1 levels at the start of infection, while later upregulation had no negative impact, suggesting distinct temporal roles of SPOC1 during the HCMV replicative cycle. Mechanistically, we observed a highly specific association of SPOC1 with the major immediate early promoter (MIEP), strongly suggesting that SPOC1 inhibits HCMV replication by MIEP binding and the subsequent recruitment of heterochromatin-building factors. Thus, our data add SPOC1 as a novel factor to the endowment of a host cell to restrict cytomegalovirus infections.IMPORTANCEAccumulating evidence indicates that during millennia of coevolution, host cells have developed a sophisticated compilation of cellular factors to restrict cytomegalovirus infections. Defining this equipment is important to understand cellular barriers against viral infection and to develop strategies to utilize these factors for antiviral approaches. So far, constituents of PML nuclear bodies and interferon gamma-inducible protein 16 (IFI16) were known to mediate intrinsic immunity against HCMV. In this study, we identify the chromatin modulator SPOC1 as a novel restriction factor against HCMV. We show that preexisting high SPOC1 protein levels mediate a silencing of HCMV gene expression via a specific association with an important viralcis-regulatory element, the major immediate early promoter. Since SPOC1 expression varies between cell types, this factor may play an important role in tissue-specific defense against HCMV.
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影响因子：
5.8
作者：
Hofmann S;Dehn S;Businger R;Bolduan S;Schneider M;Debyser Z;Brack-Werner R;Schindler M
通讯作者：
Schindler M
免疫球蛋白 A 肾病中巨细胞病毒抗体的非特异性系膜染色
DOI：
10.1016/s0140-6736(89)91144-6
发表时间：
1989
期刊：
The Lancet
影响因子：
--
作者：
F. Waldo;M. Tomana;W. Britt;B. Julian;J. Mestecky
通讯作者：
J. Mestecky
将 EYFP-pp71 (UL82) 编码序列插入人类巨细胞病毒基因组中可产生具有增强病毒生长的重组病毒
影响因子：
5.4
作者：
Nina Tavalai;M. Kraiger;Nina Kaiser;T. Stamminger
通讯作者：
T. Stamminger
影响因子：
7.7
作者：
Chung, Ho-Ryun;Xu, Chao;Kinkley, Sarah
通讯作者：
Kinkley, Sarah
DOI：
10.1073/pnas.0511148103
发表时间：
2006-02-21
影响因子：
11.1
作者：
Gaspar, M;Shenk, T
通讯作者：
Shenk, T