Yersinia YopJ Acetylates and Inhibits Kinase Activation by Blocking Phosphorylation

Abstract

Yersinia species use a variety of type III effector proteins to target eukaryotic signaling systems. The effector YopJ inhibits mitogen-activated protein kinase (MAPK) and the nuclear factor kappaB (NFkappaB) signaling pathways used in innate immune response by preventing activation of the family of MAPK kinases (MAPKK). We show that YopJ acted as an acetyltransferase, using acetyl-coenzyme A (CoA) to modify the critical serine and threonine residues in the activation loop of MAPKK6 and thereby blocking phosphorylation. The acetylation on MAPKK6 directly competed with phosphorylation, preventing activation of the modified protein. This covalent modification may be used as a general regulatory mechanism in biological signaling.

Modulation of dendritic cell differentiation and function by YopJ of Yersinia pestis

“…A more insidious effect of Yersinia infection on DC function is suggested by the following observations: (i) inhibition of the NF-jB (especially the NF-jB family member Rel B) and the MAPK (ERK) signaling pathways during progenitor to DC differentiation cripples the function of the resulting DC [20,21], and in fact NF-jB inhibition yields regulatory DC [22], (ii) Yersinia effectively injects Yops into myeloid DC progenitors that are abundant at the site of infection (and the infected draining lymph nodes, bubos) and may be triggered to undergo DC differentiation by the inflammatory cytokine microenvironment, and (iii) YopJ has a ubiquitin-like cysteine protease and acetyltransferase activity that inhibits activation of MAP kinase kinases (MKKs) and NF-jB signaling in vitro and in macrophages [23,24]. Together these findings suggest that Yersinia may not only disable existing DC, but also cripple the function of new DC being produced to replace the existing DC.…”

Identification of a host 14-3-3 protein that interacts with Xanthomonas effector AvrRxv

“…Seventeen effectors have been confirmed in Xcv [71], with only a few characterized for molecular or biochemical function. Several members of the YopJ/AvrRxv family of effectors have been shown to use a catalytic triad to target host proteins [8,13,22,25]. In this study, we used the yeast two-hybrid interaction screen to identify the protein(s) with which AvrRxv physically interacts in tomato.…”

“…Recent studies suggest that YopJ and VopP are acetyltransferases, which regulate signaling by interfering with phosphorylation [25]. Previously, it was hypothesized that family members were similar to cysteine proteases [8,26,27].…”

“…Previously, it was hypothesized that family members were similar to cysteine proteases [8,26,27]. Apparently, the catalytic triad that is conserved in all members of the family, may have acetyltransferase rather than protease activity [25]. Mutation of any amino acid in the triad results in loss of function in YopJ, AvrBsT, AvrRxv and AvrXv4 [8,13,23].…”

“…Mutation of any amino acid in the triad results in loss of function in YopJ, AvrBsT, AvrRxv and AvrXv4 [8,13,23]. It is not clear how to interpret analyses indicating that YopJ and AvrXv4 disrupt SUMO post-translation modifications in host cells [8,13], except possibly by affecting expression levels [25]. In mammalian hosts, YopJ exerts its effect on several known signal transduction pathways, thereby preventing an immune response [28][29][30][31][32][33].…”