The Shigella kinase effector OspG modulates host ubiquitin signaling to escape septin-cage entrapment

Wei Xian, Jiaqi Fu, Qinxin Zhang, Chuang Li, Yan-Bo Zhao, Zhiheng Tang, Yi Yuan, Ying Wang, Yan Zhou, Peter S. Brzoic, Ning Zheng, Songying Ouyang, Zhao-qing Luo () and Xiaoyun Liu ()
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Wei Xian: NHC Key Laboratory of Medical Immunology, School of Basic Medical Sciences, Peking University Health Science Center
Jiaqi Fu: State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, The First Hospital of Jilin University
Qinxin Zhang: NHC Key Laboratory of Medical Immunology, School of Basic Medical Sciences, Peking University Health Science Center
Chuang Li: Purdue University
Yan-Bo Zhao: 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
Zhiheng Tang: NHC Key Laboratory of Medical Immunology, School of Basic Medical Sciences, Peking University Health Science Center
Yi Yuan: NHC Key Laboratory of Medical Immunology, School of Basic Medical Sciences, Peking University Health Science Center
Ying Wang: NHC Key Laboratory of Medical Immunology, School of Basic Medical Sciences, Peking University Health Science Center
Yan Zhou: College of Life Sciences, Zhejiang University
Peter S. Brzoic: University of Washington
Ning Zheng: University of Washington
Songying Ouyang: 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
Xiaoyun Liu: NHC Key Laboratory of Medical Immunology, School of Basic Medical Sciences, Peking University Health Science Center

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Shigella flexneri is a Gram-negative bacterium causing severe bloody dysentery. Its pathogenesis is largely dictated by a plasmid-encoded type III secretion system (T3SS) and its associated effectors. Among these, the effector OspG has been shown to bind to the ubiquitin conjugation machinery (E2~Ub) to activate its kinase activity. However, the cellular targets of OspG remain elusive despite years of extensive efforts. Here we show by unbiased phosphoproteomics that a major target of OspG is CAND1, a regulatory protein controlling the assembly of cullin-RING ubiquitin ligases (CRLs). CAND1 phosphorylation weakens its interaction with cullins, which is expected to impact a large panel of CRL E3s. Indeed, global ubiquitome profiling reveals marked changes in the ubiquitination landscape when OspG is introduced. Notably, OspG promotes ubiquitination of a class of cytoskeletal proteins called septins, thereby inhibiting formation of cage-like structures encircling cytosolic bacteria. Overall, we demonstrate that pathogens have evolved an elaborate strategy to modulate host ubiquitin signaling to evade septin-cage entrapment.

Date: 2024
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DOI: 10.1038/s41467-024-48205-4

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