Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation.
Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation.
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DOI：
10.1371/journal.ppat.1004058
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发表时间：
2014-05
期刊：
影响因子：
6.7
通讯作者：
Tomasec P
中科院分区：
文献类型：
--
作者：
Fielding CA;Aicheler R;Stanton RJ;Wang EC;Han S;Seirafian S;Davies J;McSharry BP;Weekes MP;Antrobus PR;Prod'homme V;Blanchet FP;Sugrue D;Cuff S;Roberts D;Davison AJ;Lehner PJ;Wilkinson GW;Tomasec P
NKG 2D通过调节自然杀伤（NK）细胞、αβ和γδ T细胞功能在控制免疫应答中发挥重要作用。这种激活受体识别由细胞应激诱导的八种不同配体（MHC I类多肽相关序列（MIC）A和B，以及UL 1 - 6结合蛋白（ULBP）1-6），以促进识别受恶性转化或微生物感染干扰的细胞。对人巨细胞病毒（HCMV）的研究有助于NKG 2D配体（NKG 2DL）的鉴定和表征。HCMV立即早期（IE）基因上调NKGDL，我们现在描述的差异激活ULBP 2和云母/B分别由IE 1和IE 2。尽管通过IE功能激活，但HCMV在感染的早期和晚期都有效地抑制了NKGDL的细胞表面表达。已知免疫逃避功能UL 16、UL 142和microRNA（miR）-UL 112靶向NKG 2DL。虽然用UL 16缺失突变体感染引起MICB和ULBP 2细胞表面表达的预期增加，但UL 142的缺失对其靶云母没有类似的影响。因此，我们对病毒基因组进行了系统性筛选，以寻找靶向云母的附加功能。US 18和US 20被鉴定为新的NK细胞逃避功能，其能够独立地起作用以通过溶酶体降解促进云母降解。当US 18和US 20协同作用时，对云母表达的影响最显著。US 18和US 20是US 12基因家族中第一个被赋予功能的成员。US 12家族有10个成员，通过US 12-US 21顺序编码;这是一种遗传排列，暗示了祖先基因响应选择压力的“手风琴式”扩展。这种扩张一定是一个古老的事件，因为整个家族在旧世界猴的猿巨细胞病毒中是保守的。US 18和US 20对云母的组合效应所赋予的进化益处可能有助于维持US 12基因家族。人巨细胞病毒（HCMV）是一种疱疹病毒，感染世界上大多数人，通常不产生症状。然而，感染是终身的，必须由免疫系统控制。当免疫系统被削弱时，HCMV感染的结果可能非常严重。因此，HCMV是妊娠期间胎儿感染导致出生缺陷的主要原因，并且它可以在免疫系统减弱的人中引起严重疾病，特别是移植受体和HIV/AIDS患者。一种类型的免疫细胞，自然杀伤（NK）细胞，在控制体内异常细胞方面至关重要。它们通过识别表面有特殊应激蛋白的细胞并杀死它们来做到这一点。当细胞被HCMV感染时，它们开始产生这些应激蛋白。然而，该病毒已经进化出了通过快速阻止应激蛋白到达表面来阻止NK细胞杀死受感染细胞的方法。我们现在已经确定了两个HCMV基因，它们靶向一种主要的应激蛋白（称为云母）并导致其快速破坏。从HCMV中去除这两个基因使感染的细胞非常容易被NK细胞杀死。这一发现可能有助于开发对抗HCMV的新方法。
NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family. Human cytomegalovirus (HCMV) is a herpesvirus that infects most people in the world, usually without producing symptoms. However, infection is life-long and must be kept in check by the immune system. When the immune system is weakened, the outcome of HCMV infection can be very serious. Thus, HCMV is the major cause of birth defects resulting from infection of the fetus during pregnancy, and it can cause severe disease in people with a weakened immune system, especially transplant recipients and HIV/AIDS patients. One type of immune cell, the natural killer (NK) cell, is crucial in controlling cells in the body that are abnormal. They do this by recognizing cells, which have special stress proteins on their surface, and killing them. When cells are infected with HCMV, they start to make these stress proteins. However, the virus has evolved ways to stop NK cells from killing infected cells by quickly stopping the stress proteins from reaching the surface. We have now identified two HCMV genes that target a major stress protein (called MICA) and cause its rapid destruction. Removing these two genes from HCMV renders infected cells very susceptible to killing by NK cells. This discovery might help the development of new ways to fight HCMV.
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影响因子：
15.9
作者：
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通讯作者：
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