Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase

Ninghai Gan, Xiangkai Zhen, Yao Liu, Xiaolong Xu, Chunlin He, Jiazhang Qiu, Yancheng Liu, Grant M. Fujimoto, Ernesto S. Nakayasu, Biao Zhou, Lan Zhao, Kedar Puvar, Chittaranjan Das, Songying Ouyang () and Zhao-Qing Luo ()
Additional contact information
Ninghai Gan: Purdue University
Xiangkai Zhen: Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation, Biomedical Research Center of South China, Key Laboratory of OptoElectronic Science and Technology for Medicine of the Ministry of Education, College of Life Sciences, Fujian Normal University
Yao Liu: Purdue University
Xiaolong Xu: Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation, Biomedical Research Center of South China, Key Laboratory of OptoElectronic Science and Technology for Medicine of the Ministry of Education, College of Life Sciences, Fujian Normal University
Chunlin He: The First Hospital of Jilin University
Jiazhang Qiu: Jilin University
Yancheng Liu: Purdue University
Grant M. Fujimoto: Pacific Northwest National Laboratory
Ernesto S. Nakayasu: Pacific Northwest National Laboratory
Biao Zhou: Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation, Biomedical Research Center of South China, Key Laboratory of OptoElectronic Science and Technology for Medicine of the Ministry of Education, College of Life Sciences, Fujian Normal University
Lan Zhao: Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation, Biomedical Research Center of South China, Key Laboratory of OptoElectronic Science and Technology for Medicine of the Ministry of Education, College of Life Sciences, Fujian Normal University
Kedar Puvar: Purdue University
Chittaranjan Das: Purdue University
Songying Ouyang: Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation, Biomedical Research Center of South China, Key Laboratory of OptoElectronic Science and Technology for Medicine of the Ministry of Education, College of Life Sciences, Fujian Normal University
Zhao-Qing Luo: Purdue University

Nature, 2019, vol. 572, issue 7769, 387-391

Abstract: Abstract The bacterial pathogen Legionella pneumophila creates an intracellular niche permissive for its replication by extensively modulating host-cell functions using hundreds of effector proteins delivered by its Dot/Icm secretion system1. Among these, members of the SidE family (SidEs) regulate several cellular processes through a unique phosphoribosyl ubiquitination mechanism that bypasses the canonical ubiquitination machinery2–4. The activity of SidEs is regulated by another Dot/Icm effector known as SidJ5; however, the mechanism of this regulation is not completely understood6,7. Here we demonstrate that SidJ inhibits the activity of SidEs by inducing the covalent attachment of glutamate moieties to SdeA—a member of the SidE family—at E860, one of the catalytic residues that is required for the mono-ADP-ribosyltransferase activity involved in ubiquitin activation2. This inhibition by SidJ is spatially restricted in host cells because its activity requires the eukaryote-specific protein calmodulin (CaM). We solved a structure of SidJ–CaM in complex with AMP and found that the ATP used in this reaction is cleaved at the α-phosphate position by SidJ, which—in the absence of glutamate or modifiable SdeA—undergoes self-AMPylation. Our results reveal a mechanism of regulation in bacterial pathogenicity in which a glutamylation reaction that inhibits the activity of virulence factors is activated by host-factor-dependent acyl-adenylation.

Date: 2019
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DOI: 10.1038/s41586-019-1439-1

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