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

Nature | Jan 12, 2012

http://www.ncbi.nlm.nih.gov/pubmed/22158122

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 RIS Download

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

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