The 11S Proteasome Subunit PSME3 Is a Positive Feedforward Regulator of NF-κB and Important for Host Defense against Bacterial Pathogens.
The 11S Proteasome Subunit PSME3 Is a Positive Feedforward Regulator of NF-κB and Important for Host Defense against Bacterial Pathogens.
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DOI：
10.1016/j.celrep.2015.12.069
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发表时间：
2016-02-02
期刊：
影响因子：
8.8
通讯作者：
Wang P
中科院分区：
文献类型：
--
作者：
Sun J;Luan Y;Xiang D;Tan X;Chen H;Deng Q;Zhang J;Chen M;Huang H;Wang W;Niu T;Li W;Peng H;Li S;Li L;Tang W;Li X;Wu D;Wang P
NF-κB通路在免疫应答中起着重要作用。虽然它的调节已经被广泛研究，在这里，我们报告了一个未知的通过巨噬细胞中的Toll样受体(TLR)配体调节这一途径的前馈机制。在细菌感染期间，TLR配体通过核因子-κB介导的转录上调巨噬细胞中11S蛋白酶体亚单位PSME3的表达。反过来，PSME3通过直接与KLF2结合并破坏KLF2的稳定来增强NF-κB的转录活性，KLF2是NF-κB转录活性的负调控因子。与PSME3在NF-κB调节中的积极作用以及NF-κB途径在宿主抵御细菌感染中的重要性相一致，造血细胞中缺乏PSME3使宿主更容易受到细菌感染，并伴随着宿主组织中细菌负荷的增加。因此，本研究确定了PSME3的底物，并阐明了一种依赖蛋白降解但不依赖泛素的NF-κB调节机制，该机制对宿主防御和先天免疫至关重要。
The NF-κB pathway plays important roles in immune responses. Although its regulation has been extensively studied, here, we report an unknown feedforward mechanism for the regulation of this pathway by Toll-like receptor (TLR) ligands in macrophages. During bacterial infections, TLR ligands upregulate the expression of the 11S proteasome subunit PSME3 via NF-κB-mediated transcription in macrophages. PSME3, in turn, enhances the transcriptional activity of NF-κB by directly binding to and destabilizing KLF2, a negative regulator of NF-κB transcriptional activity. Consistent with this positive role of PSME3 in NF-κB regulation and importance of the NF-κB pathway in host defense against bacterial infections, the lack of PSME3 in hematopoietic cells renders the hosts more susceptible to bacterial infections, accompanied by increased bacterial burdens in host tissues. Thus, this study identifies a substrate for PSME3 and elucidates a proteolysis-dependent, but ubiquitin-independent, mechanism for NF-κB regulation that is important for host defense and innate immunity.