Targeting Rac1 by the Yersinia effector protein YopE inhibits caspase-1-mediated maturation and release of interleukin-1beta.
Yersinia bacteria can take control of the host cell by injecting so-called Yop effector proteins into the cytosol of the cells to which they adhere. Using Yersinia enterocolitica strains that are deficient for one or more Yops, we could show that YopE and, to a lesser extent, YopT interfere with the caspase-1-mediated maturation of prointerleukin-1beta in macrophages. In addition, overexpression of YopE and YopT was shown to prevent the autoproteolytic activation of caspase-1 in a way that is dependent on their inhibitory effect on Rho GTPases. Expression of constitutive-active or dominant-negative Rho GTPase mutants or treatment with Rho GTPase inhibitors confirmed the role of Rho GTPases and, in particular, Rac1 in the autoactivation of caspase-1. Rac1-induced caspase-1 activation was mediated by its effect on LIM kinase-1, which is targeting the actin cytoskeleton. Rac-1 and LIM kinase-1 dominant-negative mutants were shown to inhibit caspase-1 activation induced by overexpression of Asc, which is a caspase-1-activating adaptor protein. Moreover, Rac1 as well as YopE and YopT significantly modulated caspase-1 oligomerization. These results highlight a previously unknown function of Rho GTPases in the activation of caspase-1 and give new insight on the role of YopE in immune-escape mechanisms of Yersinia.
Schotte
Peter
P
Unit of Molecular Signal Transduction in Inflammation, Flanders Interuniversity Institute for Biotechnology (VIB), Ghent Unniversity, Ghent, Belgium.
Denecker
Geertrui
G
Van Den Broeke
Aeke
A
Vandenabeele
Peter
P
Cornelis
Guy R
GR
Beyaert
Rudi
R
D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000502:physiology*; D020170:Caspase 1 / Q000502:physiology*; D002460:Cell Line; D007375:Interleukin-1 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases; D054461:Lim Kinases; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology; D015008:Yersinia enterocolitica / Q000276:immunology; D020830:rac1 GTP-Binding Protein / Q000502:physiology*
D001425:Bacterial Outer Membrane Proteins; D007375:Interleukin-1; C063239:yopE protein, Yersinia; D011494:Protein Kinases; D054461:Lim Kinases; C515893:Limk1 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020170:Caspase 1; D020830:rac1 GTP-Binding Protein