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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.

Author information

1
Institute of Biochemistry II, Goethe University - Medical Faculty, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
2
Institute for Experimental Cancer Research in Pediatrics, Goethe University, Komturstrasse 3a, 60528 Frankfurt am Main, Germany.
3
German Cancer Consortium (DKTK), Heidelberg, Germany.
4
German Cancer Research Centre (DKFZ), Heidelberg, Germany.
5
Institute of Physical and Theoretical Chemistry, Goethe University, Max-von-Laue-Strasse 7, 60438 Frankfurt am Main, Germany.
6
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany.
7
Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany.
8
Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata 951-8510, Japan.

Abstract

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.

PMID:
28481361
DOI:
10.1038/nmicrobiol.2017.66
[Indexed for MEDLINE]

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