Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms

• Published in: Nature communications Vol. 15; no. 1; pp. 5953 - 13
• Main Authors: Fu, Jiaqi, Li, Siying, Guan, Hongxin, Li, Chuang, Zhao, Yan-Bo, Chen, Tao-Tao, Xian, Wei, Zhang, Zhengrui, Liu, Yao, Guan, Qingtian, Wang, Jingting, Lu, Qiuhua, Kang, Lina, Zheng, Si-Ru, Li, Jinyu, Cao, Shoujing, Das, Chittaranjan, Liu, Xiaoyun, Song, Lei, Ouyang, Songying, Luo, Zhao-Qing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.07.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/95; 14; 631/326/41; 631/326/41/88; 631/326/421; 631/45/612/645; 82/58; 82/83; Actin; Actins - metabolism; Adenosine Diphosphate Ribose - metabolism; ADP-Ribosylation; Bacteria; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Catalytic converters; Effectors; Functionals; HEK293 Cells; HeLa Cells; Homeostasis; Host-Pathogen Interactions; Humanities and Social Sciences; Humans; Legionella pneumophila; Legionella pneumophila - metabolism; Legionella pneumophila - pathogenicity; Legionnaires' Disease - metabolism; Legionnaires' Disease - microbiology; Legionnaires' disease bacterium; multidisciplinary; Pathogens; Proteins; Ribose; Science; Science (multidisciplinary); Toxins; Tyrosine; Ubiquitin; Ubiquitin - metabolism; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50311-2

The intracellular bacterial pathogen Legionella pneumophila modulates host cell functions by secreting multiple effectors with diverse biochemical activities. In particular, effectors of the SidE family interfere with host protein ubiquitination in a process that involves production of phosphoribosyl ubiquitin (PR-Ub). Here, we show that effector LnaB converts PR-Ub into ADP-ribosylated ubiquitin, which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by actin, LnaB also undergoes self-AMPylation on tyrosine residues. The activity of LnaB requires a motif consisting of Ser, His and Glu (SHxxxE) present in a large family of toxins from diverse bacterial pathogens. Thus, our study sheds light on the mechanisms by which a pathogen maintains ubiquitin homeostasis and identifies a family of enzymes capable of protein AMPylation. The bacterial pathogen Legionella pneumophila secretes effectors that affect protein ubiquitination within host cells, involving production of phosphoribosyl ubiquitin (PR-Ub). Here, the authors identify additional effectors that convert PR-Ub back into functional ubiquitin, thus maintaining ubiquitin homeostasis in infected cells.