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

• Published in: Nature communications Vol. 15; no. 1; pp. 3890 - 15
• Main Authors: Xian, Wei, Fu, Jiaqi, Zhang, Qinxin, Li, Chuang, Zhao, Yan-Bo, Tang, Zhiheng, Yuan, Yi, Wang, Ying, Zhou, Yan, Brzoic, Peter S., Zheng, Ning, Ouyang, Songying, Luo, Zhao-qing, Liu, Xiaoyun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.05.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 14/19; 42/35; 49/47; 631/1647/2067; 631/326/421; 631/326/88; 82/58; 82/83; Bacteria; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Cages; Conjugation; Cullin; Cullin Proteins - metabolism; Cytoskeleton; Dysentery; Dysentery, Bacillary - metabolism; Dysentery, Bacillary - microbiology; Entrapment; Gram-negative bacteria; HEK293 Cells; HeLa Cells; Host-Pathogen Interactions; Humanities and Social Sciences; Humans; Kinases; multidisciplinary; Pathogenesis; Phosphorylation; Proteins; Science; Science (multidisciplinary); Septin; Septins - genetics; Septins - metabolism; Shigella; Shigella flexneri - metabolism; Shigella flexneri - pathogenicity; Signal Transduction; Ubiquitin; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Waterborne diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48205-4

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. Here, Xian et al. use phosphoproteomics to identify that the Shigella effector OspG interacts with a regulator of Cullin-RING ubiquitin ligases to promote the ubiquitination of septins and consequent inhibition of septin cage formation.