Ubiquitin-mediated Regulation of CD86 Protein Expression by the Ubiquitin Ligase Membrane-associated RING-CH-1 (MARCH1)
Ubiquitin-mediated Regulation of CD86 Protein Expression by the Ubiquitin Ligase Membrane-associated RING-CH-1 (MARCH1)
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DOI：
10.1074/jbc.m110.204040
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发表时间：
2011-10-28
影响因子：
4.8
通讯作者：
Lybarger, Lonnie
中科院分区：
文献类型：
--
作者：
Corcoran, Kathleen;Jabbour, Maurice;Lybarger, Lonnie
幼稚T细胞的活化需要树突状细胞（DC）的抗原呈递，并且抗原呈递过程在DC成熟过程中受到调节。这种调节的一个关键方面是在DC成熟后肽中心点MHC-II复合物和共刺激分子CD 86的细胞表面上调。现在清楚的是，这些关键的诱导事件涉及E3连接酶膜相关的RING-CH-1（MARCH 1）对MHC-II和CD 86的泛素依赖性运输的变化。虽然MHC-II的泛素依赖性运输已经得到很好的表征，但关于CD 86表达的转录后调控知之甚少。在这里，我们研究了CD 86和MARCH 1之间的物理和功能相互作用。我们观察到，在MARCH 1存在下，CD 86被快速内吞，随后发生溶酶体依赖性降解。此外，我们发现CD 86和MARCH 1之间的关联主要是由各自蛋白质的跨膜结构域赋予的。与在胞质结构域中具有单个保守的泛素受体位点的MHC-II相反，我们发现在CD 86的胞质尾部中的多个赖氨酸残基可以支持泛素化，这与在CD 86胞质结构域中跨物种相对缺乏序列保守性一致。这些发现表明，MARCH 1通过跨膜结构域介导的相互作用招募多个底物，以允许底物在面对不同的胞质结构域序列时泛素化。
The activation of naive T cells requires antigen presentation by dendritic cells (DCs), and the process of antigen presentation is regulated over the course of DC maturation. One key aspect of this regulation is the cell surface up-regulation upon DC maturation of peptide center dot MHC-II complexes and the costimulatory molecule CD86. It is now clear that these critical induction events involve changes in ubiquitin-dependent trafficking of MHC-II and CD86 by the E3 ligase membrane-associated RING-CH-1 (MARCH1). Although ubiquitin-dependent trafficking of MHC-II has been well characterized, much less is known regarding the post-transcriptional regulation of CD86 expression. Here, we examined the physical and functional interaction between CD86 and MARCH1. We observed that CD86 is rapidly endocytosed in the presence of MARCH1 followed by lysosome-dependent degradation. Furthermore, we found that the association between CD86 and MARCH1 was conferred primarily by the transmembrane domains of the respective proteins. In contrast to MHC-II, which has a single, conserved ubiquitin acceptor site in the cytosolic domain, we found that multiple lysine residues in the cytosolic tail of CD86 could support ubiquitination consistent with the relative lack of sequence conservation across species within the CD86 cytosolic domain. These findings suggest that MARCH1 recruits multiple substrates via transmembrane domain-mediated interactions to permit substrate ubiquitination in the face of diverse cytosolic domain sequences.