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Title: Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase

Abstract

The bacterial pathogen Legionella pneumophila creates an intracellular niche permissive for its replication by extensively modulating the function of host cells using hundreds of effector proteins delivered via its Dot/Icm secretion system1. Among these, members of the SidE family (SidEs) regulate multiple cellular processes by a unique phosphoribosyl ubiquitination mechanism that bypasses the requirement of ATP and the E1, E2 enzymes of the canonical ubiquitination machinery2-4. The activity of SidEs is regulated by SidJ, another Dot/Icm effector5, but the mechanism of such regulation is not completely understood6,7. Here we demonstrate that SidJ functions to inhibit the activity of SidEs by inducing covalent attachment of a glutamate moiety to Glu860 of SdeA, which is one of the catalytic residues for the mono-ADP-ribosyltransferase activity involved in ubiquitin activation2. Furthermore, we found that the inhibition of SidEs activity by SidJ is restricted in host cells and such spatial regulation is achieved by the requirement of calmodulin (CaM), a eukaryote-specific protein, for its activity. Our results reveal a novel mechanism of regulation in bacterial virulence that features a posttranslational modification and its dependence upon a co-factor specific for host cells.

Authors:
 [1];  [2];  [1];  [2];  [3];  [3];  [1];  [4]; ORCiD logo [4];  [2];  [2];  [1];  [1];  [2];  [1]
  1. Purdue University
  2. Fujian Normal University
  3. Jilin University
  4. BATTELLE (PACIFIC NW LAB)
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1572484
Report Number(s):
PNNL-SA-142888
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Nature
Additional Journal Information:
Journal Volume: 572; Journal Issue: 7769
Country of Publication:
United States
Language:
English

Citation Formats

Gan, Ninghai, Zhen, Xiangkai, Liu, Yao, Xu, Xiaolong, He, Chunlin, Qiu, Jiazhang, Liu, Yancheng, Fujimoto, Grant M., Nakayasu, Ernesto S., Zhou, Biao, Zhao, Lan, Puvar, Kedar, Das, Chittaranjan, Ouyang, Songying, and Luo, Zhao-Qing. Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase. United States: N. p., 2019. Web. doi:10.1038/s41586-019-1439-1.
Gan, Ninghai, Zhen, Xiangkai, Liu, Yao, Xu, Xiaolong, He, Chunlin, Qiu, Jiazhang, Liu, Yancheng, Fujimoto, Grant M., Nakayasu, Ernesto S., Zhou, Biao, Zhao, Lan, Puvar, Kedar, Das, Chittaranjan, Ouyang, Songying, & Luo, Zhao-Qing. Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase. United States. doi:10.1038/s41586-019-1439-1.
Gan, Ninghai, Zhen, Xiangkai, Liu, Yao, Xu, Xiaolong, He, Chunlin, Qiu, Jiazhang, Liu, Yancheng, Fujimoto, Grant M., Nakayasu, Ernesto S., Zhou, Biao, Zhao, Lan, Puvar, Kedar, Das, Chittaranjan, Ouyang, Songying, and Luo, Zhao-Qing. Thu . "Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase". United States. doi:10.1038/s41586-019-1439-1.
@article{osti_1572484,
title = {Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase},
author = {Gan, Ninghai and Zhen, Xiangkai and Liu, Yao and Xu, Xiaolong and He, Chunlin and Qiu, Jiazhang and Liu, Yancheng and Fujimoto, Grant M. and Nakayasu, Ernesto S. and Zhou, Biao and Zhao, Lan and Puvar, Kedar and Das, Chittaranjan and Ouyang, Songying and Luo, Zhao-Qing},
abstractNote = {The bacterial pathogen Legionella pneumophila creates an intracellular niche permissive for its replication by extensively modulating the function of host cells using hundreds of effector proteins delivered via its Dot/Icm secretion system1. Among these, members of the SidE family (SidEs) regulate multiple cellular processes by a unique phosphoribosyl ubiquitination mechanism that bypasses the requirement of ATP and the E1, E2 enzymes of the canonical ubiquitination machinery2-4. The activity of SidEs is regulated by SidJ, another Dot/Icm effector5, but the mechanism of such regulation is not completely understood6,7. Here we demonstrate that SidJ functions to inhibit the activity of SidEs by inducing covalent attachment of a glutamate moiety to Glu860 of SdeA, which is one of the catalytic residues for the mono-ADP-ribosyltransferase activity involved in ubiquitin activation2. Furthermore, we found that the inhibition of SidEs activity by SidJ is restricted in host cells and such spatial regulation is achieved by the requirement of calmodulin (CaM), a eukaryote-specific protein, for its activity. Our results reveal a novel mechanism of regulation in bacterial virulence that features a posttranslational modification and its dependence upon a co-factor specific for host cells.},
doi = {10.1038/s41586-019-1439-1},
journal = {Nature},
number = 7769,
volume = 572,
place = {United States},
year = {2019},
month = {8}
}

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