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Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase

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  • 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
    Pilot National Laboratory for Marine Science and Technology (Qingdao))

  • 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
    Pilot National Laboratory for Marine Science and Technology (Qingdao))

  • Zhao-Qing Luo

    (Purdue University)

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.

Suggested Citation

  • 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 & Songy, 2019. "Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase," Nature, Nature, vol. 572(7769), pages 387-391, August.
    • Handle: RePEc:nat:nature:v:572:y:2019:i:7769:d:10.1038_s41586-019-1439-1
    DOI: 10.1038/s41586-019-1439-1
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    Citations

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    Cited by:

    1. Zhengrui Zhang & Jiaqi Fu & Johannes Gregor Matthias Rack & Chuang Li & Jim Voorneveld & Dmitri V. Filippov & Ivan Ahel & Zhao-Qing Luo & Chittaranjan Das, 2024. "Legionella metaeffector MavL reverses ubiquitin ADP-ribosylation via a conserved arginine-specific macrodomain," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Kristin M. Kotewicz & Mengyun Zhang & Seongok Kim & Meghan S. Martin & Atish Roy Chowdhury & Albert Tai & Rebecca A. Scheck & Ralph R. Isberg, 2024. "Sde proteins coordinate ubiquitin utilization and phosphoribosylation to establish and maintain the Legionella replication vacuole," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Dandan Wang & Lingfang Zhu & Xiangkai Zhen & Daoyan Yang & Changfu Li & Yating Chen & Huannan Wang & Yichen Qu & Xiaozhen Liu & Yanling Yin & Huawei Gu & Lei Xu & Chuanxing Wan & Yao Wang & Songying O, 2022. "A secreted effector with a dual role as a toxin and as a transcriptional factor," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Xiangkai Zhen & Yongyu Wu & Jinli Ge & Jiaqi Fu & Le Ye & Niannian Lin & Zhijie Huang & Zihe Liu & Zhao-qing Luo & Jiazhang Qiu & Songying Ouyang, 2022. "Molecular mechanism of toxin neutralization in the HipBST toxin-antitoxin system of Legionella pneumophila," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    5. Jiaqi Fu & Siying Li & Hongxin Guan & Chuang Li & Yan-Bo Zhao & Tao-Tao Chen & Wei Xian & Zhengrui Zhang & Yao Liu & Qingtian Guan & Jingting Wang & Qiuhua Lu & Lina Kang & Si-Ru Zheng & Jinyu Li & Sh, 2024. "Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Michael Adams & Rahul Sharma & Thomas Colby & Felix Weis & Ivan Matic & Sagar Bhogaraju, 2021. "Structural basis for protein glutamylation by the Legionella pseudokinase SidJ," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    7. Minhyeong Choi & Minwoo Jeong & Sangwoo Kang & Hayoung Jeon & Donghyuk Shin, 2024. "Legionella pneumophila evades host-autophagic clearance using phosphoribosyl-polyubiquitin chains," Nature Communications, Nature, vol. 15(1), pages 1-4, December.

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