Rhesus cytomegalovirus contains functional homologues of US2, US3, US6, and US11
Rhesus cytomegalovirus contains functional homologues of US2, US3, US6, and US11
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DOI：
10.1128/jvi.79.9.5786-5798.2005
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发表时间：
2005-05-01
影响因子：
5.4
通讯作者：
Früh, K
中科院分区：
文献类型：
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作者：
Pande, NT;Powers, C;Früh, K
人类巨细胞病毒（HCMV）是通过主要的组织相容性复合物（MHC）分子颠覆抗原表现的机制的范式。由于其宿主范围有限，因此无法在动物中研究HCMV。因此，在体内抑制抗原呈递对用HCMV建立和维持感染的重要性是未知的。恒河猴（RHCMV）是一种新兴动物模型，具有HCMV感染的许多特征。 RHCMV的基因组序列最近的完成表明与HCMV具有很大的同源性。令人惊讶的是，RHCMV包含几个与MHC I抗原呈现途径的HCMV US6基因家族抑制剂的基因低。在这里，我们检查了RHCMV US6同源物（开放式读取帧RH182，-184，-185，-186，-187和-189）是否会干扰MHC I抗原处理途径。我们证明RH182和RH189的功能分别与HCMV US2和US11相似，从而介导了新合成的MHC I. US3同源物，RH184，延迟MHC I成熟。与US3不同，MHC I分子最终逃脱了RH184的保留率，因此我保持稳态的MHC表面水平保持不变。 RH185的作用与US6相似，并通过TAP抑制肽转运，因此是MHC I分子的肽载荷。因此，尽管序列保守相对较低，但RHCMV中的US6家族相关基因与HCMV免疫调节剂的保守结构特征在功能上与之密切相关。这些机制的保护意味着它们对体内免疫逃避的重要性，现在可以通过实验解决这个问题。
Human cytomegalovirus (HCMV) is a paradigm for mechanisms subverting antigen presentation by major histocompatibility complex (MHC) molecules. Due to its limited host range, HCMV cannot be studied in animals. Thus, the in vivo importance of inhibiting antigen presentation for the establishment and maintenance of infection with HCMV is unknown. Rhesus cytomegalovirus (RhCMV) is an emerging animal model that shares many of the features of HCMV infection. The recent completion of the genomic sequence of RhCMV revealed a significant degree of homology to HCMV. Strikingly, RhCMV contains several genes with low homology to the HCMV US6 gene family of inhibitors of the MHC I antigen presentation pathway. Here, we examine whether the RhCMV US6 homologues (open reading frames Rh182, -184, -185, -186, -187, and -189) interfere with the MHC I antigen-processing pathway. We demonstrate that Rh182 and Rh189 function similarly to HCMV US2 and US11, respectively, mediating the proteasomal degradation of newly synthesized MHC I. The US3 homologue, Rh184, delayed MHC I maturation. Unlike US3, MHC I molecules eventually escaped retention by Rh184, so that steady-state surface levels of MHC I remained unchanged. Rh185 acted similarly to US6 and inhibited peptide transport by TAP and, consequently, peptide loading of MHC I molecules. Thus, despite relatively low sequence conservation, US6 family-related genes in RhCMV are functionally closely related to the conserved structural features of HCMV immunomodulators. The conservation of these mechanisms implies their importance for immune evasion in vivo, a question that can now be addressed experimentally.