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Abstract

As an increasing number of novel mechanisms for NF-κB pathway inhibition by bacteria are reported, we become more aware of the diversity of interactions that mediate the host-pathogen relationship and that hold clues to development of effective anti-inflammatory therapies. Our findings on the Salmonella AvrA effector may represent an example of physiological inhibition of NF-κB activation at the level of IκB ubiquitination. Ubiquitination is an enzymatically mediated covalent modification of substrate proteins that generally results in the proteasomal degradation of the modified proteins. The ubiquitination of IκB by the SCF-βTrCP complex and its subsequent degradation is a classical example. Recently, it has become apparent that modification by ubiquitin and the closely related proteins SUMO and NEDD8 are involved in myriad other regulatory roles including signaling and intracellular trafficking. An expanding list of ubiquitin ligases and hydrolases suggests a substantial regulatory network similar to the many known cellular kinases and phosphatases. As Dr. Peek mentioned, subsequent studies will be focused on identifying the target substrate(s) acted upon by S. typhimurium AvrA. AvrA has sequence and predicted structural similarities with several other bacterial and viral proteases that are capable of cleavage of the isopeptide bond formed between ubiquitin (or ubiquitin-like) monomers and the conjugated protein (Curr Opin Microbiol 2002;5:38–43). Regulatory events mediated by ubiquitin and ubiquitin-like proteins have been implicated in at least 4 steps of the NF-κB activation pathway and in other proinflammatory signaling pathways (Nat Immunol 2002;3:20–26). Thus, potential targets of AvrA include cellular proteins required for phospho-IκB ubiquitination that are posttranslationally modified by ubiquitin, SUMO, or NEDD8. The study of ubiquitin-like proteases in bacteria with anti-inflammatory or proapoptotic effects on their host cells should reveal evolutionarily conserved regulatory mechanisms that may be fruitful targets for anti-inflammatory drug discovery. As Dr. Peek pointed out, isogenic inactivation of avrA partially reversed inhibition of IL-8 secretion induced by wild-type nonpathogenic strains, but the effect was incomplete, raising the possibility that there may be other bacterial mediators contributing to the suppression of IκB ubiquitination. The recent publication of the genomic sequences of Salmonella and other enteric pathogens will greatly facilitate the search for candidate bacterial effector proteins with similar function.