Downregulation of major histocompatibility complex class I by human ubiquitin ligases related to viral immune evasion proteins
Downregulation of major histocompatibility complex class I by human ubiquitin ligases related to viral immune evasion proteins
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DOI：
10.1128/jvi.78.3.1109-1120.2004
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发表时间：
2004-02-01
影响因子：
5.4
通讯作者：
Früh, K
中科院分区：
文献类型：
--
作者：
Bartee, E;Mansouri, M;Früh, K
痘病毒和γ-2疱疹病毒共享抑制糖蛋白如主要组织相容性复合物I类（MHC-I）、B7.2、ICAM-1和CD 95（Fas）的表面表达的病毒免疫逃避蛋白的K3家族。K3家族蛋白含有氨基末端PHD/RING-CH结构域，随后是两个跨膜结构域。为了研究人类同源物是否与病毒免疫evasins功能相关，我们研究了7种膜相关RING-CH（MARCH）蛋白。所有的MARCH蛋白都位于亚细胞膜上，几种MARCH蛋白降低了病毒K3家族已知底物的表面水平。两个密切相关的蛋白质，MARCH-IV和MARCH-IX，减少了MHC-I分子的表面表达。在MARCH-IV或MARCH-IX的存在下，MHC-I被泛素化并通过内吞作用迅速内化，而在其胞质尾区缺乏赖氨酸的MHC-I分子对下调具有抗性。氨基末端区域含有RING-CH结构域的几个MARCH蛋白检测催化多泛素形成在体外，表明MARCH蛋白是泛素连接酶。MARCH家族和K3家族的功能相似性表明病毒免疫逃避蛋白源自MARCH蛋白，MARCH蛋白是一种新型跨膜泛素连接酶家族，其似乎通过胞质尾的泛素化靶向糖蛋白用于溶酶体破坏。
Poxviruses and gamma-2 herpesviruses share the K3 family of viral immune evasion proteins that inhibit the surface expression of glycoproteins such as major histocompatibility complex class I (MHC-I), B7.2, ICAM-1, and CD95(Fas). K3 family proteins contain an amino-terminal PHD/LAP or RING-CH domain followed by two transmembrane domains. To examine whether human homologues are functionally related to the viral immunoevasins, we studied seven membrane-associated RING-CH (MARCH) proteins. All MARCH proteins located to subcellular membranes, and several MARCH proteins reduced surface levels of known substrates of the viral K3 family. Two closely related proteins, MARCH-IV and MARCH-IX, reduced surface expression of MHC-I molecules. In the presence of MARCH-IV or MARCH-IX, MHC-I was ubiquitinated and rapidly internalized by endocytosis, whereas MHC-I molecules lacking lysines in their cytoplasmic tail were resistant to downregulation. The amino-terminal regions containing the RING-CH domain of several MARCH proteins examined catalyzed multiubiquitin formation in vitro, suggesting that MARCH proteins are ubiquitin ligases. The functional similarity of the MARCH family and the K3 family suggests that the viral immune evasion proteins were derived from MARCH proteins, a novel family of transmembrane ubiquitin ligases that seems to target glycoproteins for lysosomal destruction via ubiquitination of the cytoplasmic tail.