The ORF45 Protein of Kaposi Sarcoma-Associated Herpesvirus Is an Inhibitor of p53 Signaling during Viral Reactivation
The ORF45 Protein of Kaposi Sarcoma-Associated Herpesvirus Is an Inhibitor of p53 Signaling during Viral Reactivation
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DOI：
10.1128/jvi.01459-21
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发表时间：
2021-12-01
影响因子：
5.4
通讯作者：
Dittmer, Dirk P.
中科院分区：
文献类型：
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作者：
Alzhanova, Dina;Meyo, James O.;Dittmer, Dirk P.
Kaposi肉瘤相关疱疹病毒(KSHV)是一种致癌双链DNA病毒，是Kaposi肉瘤(KS)、原发性渗出性淋巴瘤(PEL)和多中心Castleman病(MCD)的病原体。为了防止过早的细胞凋亡并支持其复制周期，KSHV表达一系列开放阅读框架(ORF)，通过P53肿瘤抑制蛋白调节信号。在这里，我们描述了一种新的由KSHV ORF45编码的P53病毒抑制物，并确定了其作用机制。ORF45与P53结合并阻止其与P53脱泛素酶USP7的相互作用。这导致P53积聚减少，P53定位于细胞质，转录活性降低。与其他癌症不同，肿瘤抑制蛋白P53在卡波西肉瘤(KS)中很少发生突变。相反，卡波西肉瘤相关疱疹病毒(KSHV)通过多种病毒蛋白使P53失活。KS的一种可能的治疗方法是激活P53，这将导致细胞凋亡和肿瘤消退。在这一点上，重要的是要了解KSHV用来调节p53信号的所有机制。这项工作描述了一种新的P53信号转导抑制剂和一个潜在的药物靶点ORF45，并确定了其作用机制。
Kaposi sarcoma-associated herpesvirus (KSHV) is a carcinogenic double stranded DNA virus and the etiological agent of Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). To prevent premature apoptosis and support its replication cycle, KSHV expresses a series of open reading frames (ORFs) that regulate signaling by the p53 tumor suppressor protein. Here, we describe a novel viral inhibitor of p53 encoded by KSHV ORF45 and identify its mechanism of action. ORF45 binds to p53 and prevents its interactions with USP7, a p53 deubiquitinase. This results in decreased p53 accumulation, localization of p53 to the cytoplasm, and diminished transcriptional activity.IMPORTANCE Unlike in other cancers, the tumor suppressor protein p53 is rarely mutated in Kaposi sarcoma (KS). Rather, Kaposi sarcoma-associated herpesvirus (KSHV) inactivates p53 through multiple viral proteins. One possible therapeutic approach to KS is the activation of p53, which would result in apoptosis and tumor regression. In this regard, it is important to understand all the mechanisms used by KSHV to modulate p53 signaling. This work describes a novel inhibitor of p53 signaling and a potential drug target, ORF45, and identifies the mechanisms of its action.