Nε-Fatty acylation of Rho GTPases by a MARTX toxin effector

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Science  27 Oct 2017:
Vol. 358, Issue 6362, pp. 528-531
DOI: 10.1126/science.aam8659

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Bacterial toxin fatty-acylates lysine residues

A toxin produced by the bacterium that causes cholera has a catalytic activity that contributes to its effects on the cytoskeleton of host cells. Zhou et al. determined the protein structure of the Rho guanosine triphosphatase (GTPase)–inactivation domain of the toxin from Vibrio cholerae and found it to be similar to that of a human fatty acyltransferase. Indeed, the toxin peptide could catalyze fatty acylation of lysine residues of Rho-family GTPases, which regulate the actin cytoskeleton. Such covalent modification of lysine residues in mammalian proteins had been noted before, but the enzymes responsible were not known.

Science, this issue p. 528


The multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are a family of large toxins that are extensively distributed in bacterial pathogens. MARTX toxins are autocatalytically cleaved to multiple effector domains, which are released into host cells to modulate the host signaling pathways. The Rho guanosine triphosphatase (GTPase) inactivation domain (RID), a conserved effector domain of MARTX toxins, is implicated in cell rounding by disrupting the host actin cytoskeleton. We found that the RID is an Nε-fatty acyltransferase that covalently modifies the lysine residues in the C-terminal polybasic region of Rho GTPases. The resulting fatty acylation inhibited Rho GTPases and disrupted Rho GTPase–mediated signaling in the host. Thus, RID can mediate the lysine Nε-fatty acylation of mammalian proteins and represents a family of toxins that harbor N-fatty acyltransferase activities in bacterial pathogens.

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