Zarrella Kristen, Longmire Pierce, Zeltzer Sebastian, Collins-McMillen Donna, Hancock Meaghan, Buehler Jason, Reitsma Justin M, Terhune Scott S, Nelson Jay A, Goodrum Felicia
Department of Immunobiology, University of Arizona, Tucson, AZ 85721.
BIO5 Institute, University of Arizona, Tucson, AZ 85721.
bioRxiv. 2023 Feb 7:2023.02.07.527452. doi: 10.1101/2023.02.07.527452.
Innate immune responses are crucial for limiting virus infection. However, viruses often hijack our best defenses for viral objectives. Human Cytomegalovirus (HCMV) is a beta herpesvirus which establishes a life-long latent infection. Defining the virus-host interactions controlling latency and reactivation is vital to the control of viral disease risk posed by virus reactivation. We defined an interaction between UL138, a pro-latency HCMV gene, and the host deubiquintase complex, UAF1-USP1. UAF1 is a scaffold protein pivotal for the activity of ubiquitin specific peptidases (USP), including USP1. UAF1-USP1 sustains an innate immune response through the phosphorylation and activation of signal transducer and activator of transcription-1 (pSTAT1), as well as regulates the DNA damage response. After the onset of viral DNA synthesis, pSTAT1 levels are elevated and this depends upon UL138 and USP1. pSTAT1 localizes to viral centers of replication, binds to the viral genome, and influences UL138 expression. Inhibition of USP1 results in a failure to establish latency, marked by increased viral genome replication and production of viral progeny. Inhibition of Jak-STAT signaling also results in increased viral genome synthesis in hematopoietic cells, consistent with a role for USP1-mediated regulation of STAT1 signaling in the establishment of latency. These findings demonstrate the importance of the UL138-UAF1-USP1 virus-host interaction in regulating HCMV latency establishment through the control of innate immune signaling. It will be important going forward to distinguish roles of UAF1-USP1 in regulating pSTAT1 relative to its role in the DNA damage response in HCMV infection.
Human cytomegalovirus (HCMV) is one of nine herpesviruses that infect humans. Following a primary infection, HCMV establishes a life-long latent infection that is marked by sporadic, and likely frequent reactivation events. While these reactivation events are asymptomatic in the immune competent host, they pose important disease risks for the immune compromised, including solid organ or stem cell transplant recipients. Its complex interactions with host biology and deep coding capacity make it an excellent model for defining mechanisms important for viral latency and reactivation. Here we define an interaction with host proteins that commandeer typically antiviral innate immune signaling for the establishment of latency.
固有免疫反应对于限制病毒感染至关重要。然而，病毒常常劫持我们的最佳防御机制以实现其自身目的。人巨细胞病毒（HCMV）是一种β疱疹病毒，可建立终身潜伏感染。明确控制潜伏和再激活的病毒 - 宿主相互作用对于控制病毒再激活所带来的病毒疾病风险至关重要。我们确定了一种促潜伏的HCMV基因UL138与宿主去泛素化酶复合物UAF1 - USP1之间的相互作用。UAF1是一种支架蛋白，对包括USP1在内的泛素特异性蛋白酶（USP）的活性至关重要。UAF1 - USP1通过信号转导和转录激活因子1（pSTAT1）的磷酸化和激活维持固有免疫反应，同时还调节DNA损伤反应。在病毒DNA合成开始后，pSTAT1水平升高，这依赖于UL138和USP1。pSTAT1定位于病毒复制中心，与病毒基因组结合，并影响UL138的表达。抑制USP1会导致无法建立潜伏状态，表现为病毒基因组复制增加和病毒子代产生。抑制Jak - STAT信号传导也会导致造血细胞中病毒基因组合成增加，这与USP1介导的STAT1信号传导在潜伏建立中的作用一致。这些发现证明了UL138 - UAF1 - USP1病毒 - 宿主相互作用在通过控制固有免疫信号传导调节HCMV潜伏建立中的重要性。未来区分UAF1 - USP1在调节pSTAT1方面相对于其在HCMV感染中DNA损伤反应中的作用将很重要。
人巨细胞病毒（HCMV）是感染人类的九种疱疹病毒之一。初次感染后，HCMV建立终身潜伏感染，其特征为散发性且可能频繁的再激活事件。虽然这些再激活事件在免疫功能正常的宿主中无症状，但它们对免疫功能受损者构成重要疾病风险，包括实体器官或干细胞移植受者。它与宿主生物学的复杂相互作用以及深厚的编码能力使其成为定义病毒潜伏和再激活重要机制的极佳模型。在这里，我们确定了与宿主蛋白的一种相互作用，这种相互作用利用通常的抗病毒固有免疫信号传导来建立潜伏状态。
