Ubiquitin ligases and ubiquitin-sensing proteins have histidine and cysteine residues that coordinate the zinc atoms essential for their activity. In Nature, Zhang et al. identify the virulence factor NleE, produced by enteropathogenic Escherichia coli, that modifies zinc-binding cysteine residues in the TAB2 and TAB3 ubiquitin-binding adaptors in the kinase TAK1 complex. NleE uses S-adenosyl methionine to methylate these cysteines, which prevents further interactions via their thiol groups. After infection, NleE targets TAB2 and TAB3 to prevent their recognition of polyubiquitin chains and prevents downstream activation of the transcription factor NF-κB and the generation of antimicrobial responses. NleE activity is highly specific for TAB proteins, as it does not inhibit activity of the NF-κB modulator NEMO or components of LUBAC, the linear ubiquitin chain–assembly complex. Whether other similar cysteine methylases exist that regulate other ubiquitin-dependent signaling pathways is open to investigation.

Nature (11 December 2011) doi:10.1038/nature10690