期刊
NATURE MICROBIOLOGY
卷 2, 期 7, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nmicrobiol.2017.66
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资金
- DFG [SPP 1580, SFB 1177, EXC115]
- LOEWE programme 'Ubiquitin Networks' (Ub-Net) - State of Hesse/Germany
- LOEWE Center for Gene and Cell Therapy Frankfurt (CGT) - State of Hesse/Germany
- EMBO long-term postdoctoral fellowship
- Grants-in-Aid for Scientific Research [25111006] Funding Source: KAKEN
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.
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