To suppress a host cell's immune response, bacterial pathogens such as Salmonella, Shigella and enteropathogenic Escherichia coli (EPEC) target the NF-κB pathway. Recent work in EPEC showed that the type III secreted effector NleE can suppress NF-κB signaling and NF-κB–dependent cytokine production. NleE has orthologs in some species of Salmonella and Shigella. Shao and colleagues have now determined the mechanism by which NleE inhibits NF-κB signaling. First, they found that NleE can block NF-κB signaling initiated by TNF-α or IL-1β at a step downstream of the TRAF ubiquitin ligases and upstream of TAK1; more specifically, TRAF6-induced TAK1 activation was attenuated. As TRAF6-mediated ubiquitin chain formation was not affected, the authors focused on interactions within the TAK1 complex, comprising the kinase TAK1, TAB1 and the ubiquitin-chain-sensing proteins TAB2/3. TAB2/3 binding to Lys63-linked polyubiquitin chains is required for the oligomerization and autophosphorylation events involved in TAK1 kinase activation. The authors found that NleE targets the Npl4 zinc finger (NZF) domain of TAB2/3, which mediates binding to polyubiquitin chains. Additional experiments revealed that NleE is an S-adenosyl-L-methionine methyltransferase that modifies one of the four zinc-coordinating cysteine residues in the TAB2/3 NZF domain. The methylated cysteine is located at a hydrophobic surface that recognizes the Ile44 patch of ubiquitin, so the modification results in loss of ubiquitin binding activity. As zinc binding renders cysteine a better methyl acceptor, and given the prevalence of the zinc-finger motif in many proteins, the authors suggest methylation of a zinc-finger cysteine may play a more widespread but previously unrecognized role in modulating signal transduction. (Nature doi:10.1038/nature10690, published online 11 December 2011)