Linear ubiquitination of cytosolic Salmonella Typhimurium activates NF-κB and restricts bacterial proliferation
Linear ubiquitination of cytosolic Salmonella Typhimurium activates NF-κB and restricts bacterial proliferation
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DOI：
10.1038/nmicrobiol.2017.66
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发表时间：
2017-07-01
影响因子：
28.3
通讯作者：
Dikic, Ivan
中科院分区：
文献类型：
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作者：
van Wijk, Sjoerd J. L.;Fricke, Franziska;Dikic, Ivan
入侵鼠伤寒沙门氏菌的泛素化引发胞质细菌的自噬并限制其在上皮细胞中的扩散。泛素（Ub）链募集自噬受体，如p62/SQSTM1、NDP52/CALCOCO和OPTN，这些自噬受体启动双膜自噬体结构的形成和溶酶体的破坏，这一过程被称为异噬。除此之外，宿主-沙门氏菌界面上差异连接的Ub链的功能后果和机制调节仍未被探索。在这里，我们首次表明，胞质鼠伤寒沙门氏菌上不同的Ub链作为触发进一步信号级联的平台。通过单分子定位显微镜，我们可视化了鼠伤寒沙门氏菌胞质表面线性（m1连接）Ub链形成的平衡和纳米尺度分布模式。此外，我们还发现脱泛素酶OTULIN是细菌外壳上这些m1连接的Ub链的中心调节剂。OTULIN的缺失导致线性Ub链的形成增强，导致NEMO的局部募集，IKK α /IKK β的激活，最终导致NF-kappa B的激活，进而促进促炎细胞因子的分泌，限制细菌增殖。我们的研究结果证实了鼠伤寒沙门氏菌胞质周围的线性Ub包被作为局部NF-kappa B信号传导平台的作用，并为OTULIN在细菌发病过程中NF-kappa B激活中的功能提供了新的见解。
Ubiquitination of invading Salmonella Typhimurium triggers autophagy of cytosolic bacteria and restricts their spread in epithelial cells. Ubiquitin (Ub) chains recruit autophagy receptors such as p62/SQSTM1, NDP52/CALCOCO and optineurin (OPTN), which initiate the formation of double-membrane autophagosomal structures and lysosomal destruction in a process known as xenophagy. Besides this, the functional consequences and mechanistic regulation of differentially linked Ub chains at the host-Salmonella interface have remained unexplored. Here, we show, for the first time, that distinct Ub chains on cytosolic S. Typhimurium serve as a platform triggering further signalling cascades. By using single-molecule localization microscopy, we visualized the balance and nanoscale distribution pattern of linear (M1-linked) Ub chain formation at the surface of cytosolic S. Typhimurium. In addition, we identified the deubiquitinase OTULIN as central regulator of these M1-linked Ub chains on the bacterial coat. OTULIN depletion leads to enhanced formation of linear Ub chains, resulting in local recruitment of NEMO, activation of IKK alpha/IKK beta and ultimately NF-kappa B, which in turn promotes secretion of pro-inflammatory cytokines and restricts bacterial proliferation. Our results establish a role for the linear Ub coat around cytosolic S. Typhimurium as the local NF-kappa B signalling platform and provide insights into the function of OTULIN in NF-kappa B activation during bacterial pathogenesis.