Li Zhang, 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
Graduate Program in Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Nature 2012 Jan 12NF-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.
Li Zhang, 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. Cysteine methylation disrupts ubiquitin-chain sensing in NF-κB activation. Nature. 2012 Jan 12;481(7380):204-8
PMID: 22158122
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