Molecular Mechanisms of Major histocompatibility complex (MHC) gene regulation

我的研究项目主要集中在控制主要组织相容性复合体（MHC;人类HLA）I类（MHC-I）和II类（MHC-II）基因和蛋白质表达的多种调控机制。MHC分子是向T细胞展示肽抗原的抗原呈递分子，因此对于适应性免疫应答至关重要。MHC依赖性免疫应答受到复杂的调节。MHC-II反式激活因子CIITA是NLR（核苷酸结合和富含亮氨酸重复序列）蛋白家族的成员，是MHC-II基因表达的主要调节因子。我们最近发现CIITA的蛋白质周转与其激活转录的能力直接相关。CIITA同种型III的前10个氨基酸充当便携式降解决定子和反式激活序列。CIITA同种型III的N-末端负责增加与转录机制组分的相互作用。这些实验揭示了蛋白质的游离N-末端在降解依赖的转录激活中的新功能。

My research program is focused on the multiple regulatory mechanisms that control major histocompatibility complex (MHC; HLA in human) class I (MHC-I) and class II (MHC-II) gene and protein expression. MHC molecules are antigen-presenting molecules displaying peptide antigens to T cells, and are thus of central importance for the adaptive immune response. MHC-dependent immune responses are intricately regulated. The MHC-II transactivator CIITA, a member of the NLR (nucleotide binding and leucine rich repeats) family of proteins, is the master regulator of MHC-II gene expression. We have found recently that protein turnover of CIITA is directly linked to its capacity to activate transcription. The first ten amino acids of CIITA isoform III act as a portable degron and transactivation sequence. The N-terminal end of CIITA isoform III is responsible for increased interaction with components of the transcription machinery. These experiments reveal a novel function of free N-terminal ends of proteins in degradation-dependent transcriptional activation.