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Yongqun Zhu Lab, Science: Nε-Fatty Acylation of Rho GTPases by a MARTX Toxin Effector


On October 27, 2017, Dr. Yongqun Zhu laboratory published a research paper in Science entitled “Nε-Fatty Acylation of Rho GTPases by a MARTX Toxin Effector”, which describes that a unique posttranslational modification of Rho GTPases catalyzed by a MARTX toxin effector inhibits Rho GTPases and disrupts the host Rho GTPase-mediated signaling.

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.

Figure. The molecular mechanism of Rac1 Inactivation by RID

Fatty acyltransferase activity of RID modifies host Rac1 GTPase. (A) Fatty acylation of Rac1 Q61L by RID from V. cholerae (RIDvc) in vivo. Fatty acylation of Rac1 was detected via click chemistry reactions and Western blotting with a streptavidin-biotinylated horseradish peroxidase complex. (B) Fatty acylation of Rac1LS by RID in vitro. (C) Fatty acylation of wild-type Rac1LS and Rac1LS Q61L, in contrast to inactive Rac1 T17N, by RID in vitro. (D) Fatty acylation of Rac1Q61L by RID during V. cholerae infection.

Yan Zhou and Chunfeng Huang are the first authors, and Dr. Yongqun Zhu is the corresponding author of this paper. This study was collaborated by Drs. Feng Shao, Xiaoyun Liu and She Chen, and supported by National Natural Science Foundation of China (NSFC), Zhejiang Natural Science Foundation, Royal Society of UK, China Ministry of Science and Technology grants and the Fundamental Research Funds for the Central Universities.