Molecular mechanism and cellular function of MHCII ubiquitination.
Molecular mechanism and cellular function of MHCII ubiquitination.
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DOI：
10.1111/imr.12303
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发表时间：
2015-07
影响因子：
8.7
通讯作者：
Shin JS
中科院分区：
文献类型：
--
作者：
Oh J;Shin JS
在树突状细胞（dc）和B细胞中，主要的组织相容性复合体II类（MHCII）通过进化上保守的β链细胞质尾部赖氨酸被泛素化。在模型细胞系中，泛素化是由膜相关环- ch1 （MARCH1）泛素连接酶介导的，尽管它也可以由同源连接酶MARCH8介导。泛素化促进MHCII内吞作用和溶酶体分选，导致细胞表面MHCII水平降低。功能上，MHCII泛素化作为dc抑制MHCII表达和减少抗原呈递的一种手段，以响应免疫调节性细胞因子IL-10和调节性T细胞。最近，MHCII泛素化的其他作用已经开始出现。MHCII泛素化促进DC产生炎性细胞因子响应toll样受体配体。它还增强了DC激活抗原特异性naïve CD4+ T细胞的能力，同时限制了细胞表面抗原的数量。同样，MHCII泛素化促进DC激活CD4+胸腺细胞，支持调节性t细胞的发育，而不受限制性抗原呈递的影响。因此，泛素化似乎通过一种尚未确定的机制赋予MHCII一种独立于呈递抗原的功能。
The major histocompatibility complex class II (MHCII) is ubiquitinated via the evolutionally conserved lysine in the cytoplasmic tail of the β chain in dendritic cells (DCs) and B cells. The ubiquitination is mediated by the membrane-associated RING-CH1 (MARCH1) ubiquitin ligase although it can be also mediated by the homolog ligase MARCH8 in model cell lines. The ubiquitination promotes MHCII endocytosis and lysosomal sorting that results in a reduction in the level of MHCII at cell surface. Functionally, MHCII ubiquitination serves as a means by which DCs suppress MHCII expression and reduce antigen presentation in response to the immune-regulatory cytokine IL-10 and regulatory T cells. Recently, additional roles of MHCII ubiquitination have begun to emerge. MHCII ubiquitination promoted DC production of inflammatory cytokines in response to the Toll-like receptor ligands. It also potentiated DC ability to activate antigen-specific naïve CD4+ T cells while limiting the amount of antigens presented at cell surface. Similarly, MHCII ubiquitination promoted DC activation of CD4+ thymocytes supporting regulatory T-cell development independent of its effect of limiting antigen presentation. Thus, ubiquitination appears to confer MHCII a function independent of presenting antigens by a mechanism yet to be identified.