Plaguing Caspase-1 Through Rac

Abstract

The Yersinia bacteria, whose most notorious member ( Y. pestis ) is the organism that causes bubonic plague, inject Yop proteins into target cells. The individual Yop effectors, which cooperate to prevent phagocytosis and suppress the inflammatory response, have highly specific effects. For instance, YopP interferes with nuclear factor NF-κB activation and thus transcription of proinflammatory cytokines, whereas YopE acts as a guanosine triphosphatase (GTPase)-activating protein (GAP) for Rho-family GTPases and thereby interferes with cytoskeletal rearrangements involved in phagocytosis. Noticing that Mf4/4 murine macrophages infected with Y. enterocolitica that lacked YopP secreted more interleukin-6 (IL-6) than did macrophages infected with wild-type bacteria, but not more IL-1β, Schotte et al. discovered that the former contained increased cytoplasmic concentrations of proIL-1β. The authors used Y. enterocolitica strains lacking various Yops to show that YopE inhibited proIL-1β processing, an effect that depended on its GAP activity. ProIL-1β is converted into IL-1β by caspase-1 and, in HEK293T cells transfected with procaspase-1 and pro-IL-1β, wild-type YopE but not a catalytically inactive mutant inhibited autocatalytic processing of procaspase-1 and processing of proIL-1β. Cells expressing constitutively active Rac1 (a Rho-family GTPase) showed increased procaspase-1 autoproteolysis and secretion of IL-1β, whereas dominant-negative Rac1 or pharmacological inhibition of Rho-family GTPase activity suppressed both. Stimulation of caspase-1 by Rac1 depended on its ability to influence the organization of the actin cytoskeleton and involved caspase-1 oligomerization mediated by the adaptor protein Asc. These data underline the cooperative actions of the Yop proteins and uncover an unexpected role for Rac1 in caspase-1 activation. P. Schotte, G. Denecker, A. Van Den Broeke, P. Vandenabeele, G. R. Cornelis, R. Beyaert, Targeting Rac1 by the Yersinia effector protein YopE inhibits caspase-1-mediated maturation and release of interleukin-1β. J. Biol. Chem. 279 , 25134-25142 (2004). [Abstract] [Full Text]