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Cysteine methylation disrupts ubiquitin-chain sensing in NF-κB activation.

NF-κB is crucial for innate immune defence against microbial infection. Inhibition of NF-κB signalling has been observed with various bacterial infections. The NF-κB pathway critically requires multiple ubiquitin-chain signals of different natures. The question of whether ubiquitin-chain signalling and its specificity in NF-κB activation are regulated during infection, and how this regulation takes place, has not been explored. Here we show that human TAB2 and TAB3, ubiquitin-chain sensory proteins involved in NF-κB signalling, are directly inactivated by enteropathogenic Escherichia coli NleE, a conserved bacterial type-III-secreted effector responsible for blocking host NF-κB signalling. NleE harboured an unprecedented S-adenosyl-l-methionine-dependent methyltransferase activity that specifically modified a zinc-coordinating cysteine in the Npl4 zinc finger (NZF) domains in TAB2 and TAB3. Cysteine-methylated TAB2-NZF and TAB3-NZF (truncated proteins only comprising the NZF domain) lost the zinc ion as well as the ubiquitin-chain binding activity. Ectopically expressed or type-III-secretion-system-delivered NleE methylated TAB2 and TAB3 in host cells and diminished their ubiquitin-chain binding activity. Replacement of the NZF domain of TAB3 with the NleE methylation-insensitive Npl4 NZF domain resulted in NleE-resistant NF-κB activation. Given the prevalence of zinc-finger motifs and activation of cysteine thiol by zinc binding, methylation of zinc-finger cysteine might regulate other eukaryotic pathways in addition to NF-κB signalling.

Pubmed ID: 22158122

Authors

  • Zhang L
  • Ding X
  • Cui J
  • Xu H
  • Chen J
  • Gong YN
  • Hu L
  • Zhou Y
  • Ge J
  • Lu Q
  • Liu L
  • Chen S
  • Shao F

Journal

Nature

Publication Data

January 12, 2012

Associated Grants

None

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Bacterial Secretion Systems
  • Cysteine
  • Enteropathogenic Escherichia coli
  • Escherichia coli Proteins
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • MAP Kinase Kinase Kinases
  • Methionine
  • Methylation
  • Methyltransferases
  • NF-kappa B
  • Protein Binding
  • Protein Structure, Tertiary
  • Signal Transduction
  • Substrate Specificity
  • TNF Receptor-Associated Factor 6
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Ubiquitin
  • Virulence Factors
  • Zinc Fingers