Cysteine methylation disrupts ubiquitin-chain sensing in NF-κB activation - PubMed (original) (raw)

. 2011 Dec 11;481(7380):204-8.

doi: 10.1038/nature10690.

Xiaojun Ding, Jixin Cui, Hao Xu, Jing Chen, Yi-Nan Gong, Liyan Hu, Yan Zhou, Jianning Ge, Qiuhe Lu, Liping Liu, She Chen, Feng Shao

Affiliations

• PMID: 22158122
• DOI: 10.1038/nature10690

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

Li Zhang et al. Nature. 2011.

Abstract

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.

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References

1. 1. Annu Rev Biochem. 2009;78:769-96 - PubMed
2. 1. J Immunol. 2010 Oct 1;185(7):4118-27 - PubMed
3. 1. Annu Rev Immunol. 2009;27:693-733 - PubMed
4. 1. J Biol Chem. 2003 May 30;278(22):20225-34 - PubMed
5. 1. Nature. 2011 Mar 31;471(7340):637-41 - PubMed

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