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Nat Microbiol. 2017 May 8;2:17066. doi: 10.1038/nmicrobiol.2017.66.

Linear ubiquitination of cytosolic Salmonella Typhimurium activates NF-κB and restricts bacterial proliferation.

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Institute of Biochemistry II, Goethe University - Medical Faculty, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Institute for Experimental Cancer Research in Pediatrics, Goethe University, Komturstrasse 3a, 60528 Frankfurt am Main, Germany.
German Cancer Consortium (DKTK), Heidelberg, Germany.
German Cancer Research Centre (DKFZ), Heidelberg, Germany.
Institute of Physical and Theoretical Chemistry, Goethe University, Max-von-Laue-Strasse 7, 60438 Frankfurt am Main, Germany.
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany.
Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany.
Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata 951-8510, Japan.


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 IKKα/IKKβ and ultimately NF-κB, 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-κB signalling platform and provide insights into the function of OTULIN in NF-κB activation during bacterial pathogenesis.

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