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SseL, a Salmonella deubiquitinase required for macrophage killing and virulence

Rytkönen, Anne, Poh, John, Garmendia, Junkal, Boyle, Cliona, Thompson, Arthur, Liu, Mei, Freemont, Paul, Hinton, Jay C.D., Holden, David W.
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.9 pp. 3502-3507
Salmonella Typhimurium, bacteria, cysteine proteinases, cytokines, cytotoxicity, macrophages, mice, mutants, pathogenicity islands, regulon, secretion, transcriptomics, type III secretion system, ubiquitin, virulence
Expression of the Salmonella enterica serovar Typhimurium pathogenicity island 2 (SPI-2) type III secretion system is controlled by the two-component regulatory system SsrA-SsrB. We used a transcriptomic approach to help define the SsrA-SsrB regulon. We identified a gene encoding an uncharacterized effector (SseL) whose translocation into host cells depends on the SPI-2 secretion system. SseL has similarities to cysteine proteases with deubiquitinating activity. A GST-SseL fusion protein specifically hydrolyzed mono- and polyubiquitin substrates in vitro with a preference for K63-linked ubiquitin chains. Ubiquitin-modified proteins accumulated in macrophages infected with Salmonella sseL mutant strains but to a lesser extent when infected with bacteria expressing active protein, demonstrating that SseL functions as a deubiquitinase in vivo. Salmonella sseL mutant strains did not show a replication defect or induce altered levels of cytokine production upon infection of macrophages but were defective for a delayed cytotoxic effect and were attenuated for virulence in mice.