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

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

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.

MeSH terms

  • Autophagy
  • Cell Proliferation
  • Cytosol / metabolism
  • Cytosol / microbiology*
  • Endopeptidases / genetics
  • Endopeptidases / metabolism*
  • Epithelial Cells / microbiology
  • HEK293 Cells
  • HeLa Cells
  • Host-Pathogen Interactions / genetics
  • Host-Pathogen Interactions / physiology
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Salmonella typhimurium / metabolism*
  • Salmonella typhimurium / pathogenicity
  • Signal Transduction*
  • Ubiquitin / metabolism
  • Ubiquitination*

Substances

  • IKBKG protein, human
  • NF-kappa B
  • Ubiquitin
  • I-kappa B Kinase
  • Endopeptidases
  • gumby protein, human