本研究旨在阐明结核分枝杆菌PE_PGRS41调控LUBAC复合体介导的NF-κB激活与宿主细胞命运的分子机理。PE_PGRS41表达被酸和吞噬体调控，也称为aprC(acid and phagosome regulated protein C)。LUBAC是负责线性泛素化的唯一已知E3连接酶。基于我们前期PGRS41差异调控细胞因子表达，增强重组菌胞内存活、抑制宿主细胞凋亡，导致宿主细胞NF-κB信号通路多个组分泛素化，尤其是NEMO以及LUBAC复合体组分，活动性肺结核患者外周血单核细胞中LUBAC组分转录增强等结果，我们假设：PE_PGRS41调控LUBAC介导的NF-κB激活，改变细胞因子表达和细胞命运。项目将通过定量泛素化组，NF-κB-luc荧光素酶活性，截短/定点突变鉴定PE_PGRS41功能的关键残基或者功能域，LUBAC泛素化检测等验证假说，研究线性泛素化的作用和机理。

We aims to elucidate the molecular basis underlying the Linear ubiquitin assembly complex (LUBAC)-mediated activation of NF-κB signaling elicited by Mycobacterium tuberculosis PE_PGRS41. PE_PGRS41 is a member of PE/PPE family, also termed aprC（acid and phagosome regulated protein C）, which can be modulated by acid and phagosome. LUBAC is the sole known E3 ligase for the linear ubiquitination. Our hypothesis is that PE_PGRS41alters the LUBAC- mediated NF-κB signaling and downstream cytokines expression and cell fates. This is based on our previous results that 1. PE_PGRS41 differentially regulates the cytokines, promoted the apoptosis of host cells and recombinant Mycobacteria survival;2.Differentially ubiquitinated the components of NF-κB, especially the NEMO and LUBAC components HOIP, HOIL-1L;3. The transcription of LUBAC components was enhanced in active tuberculosis patients peripheral blood monocytes. To test the hypothesis, truncated or site-directed mutagenesis PE_PGRS41 will be used to define the critical residues or domains for this effect, the ubiquitination of LUBAC components and linear ubiquitination of NF-κB signaling components, such as the NEMO will be monitored to test this hypothesis.This will inspire the pathogenesis quest from novel perspective.