Effector-mediated ubiquitin manipulation in Legionella pneumophila pathogenesis
EMSL Project ID
50571
Abstract
Ubiquitination is catalyzed by a cascade of 3 enzymes (E1, E2 and E3) that links the carboxyl terminus of ubiquitin mainly to the side chains of lysine residues. This process controls a variety of important cellular pathway, particularly immunity. Therefore, it is not a surprise that the ubiquitin network is a common target of different pathogenic microbes. In this context, the pathogenic bacterium Legionella pneumophila, causative agent of Legionnaires’ disease, secretes an arsenal of effectors, which modulate host cellular pathways to make the intracellular environment permissive for the bacterial survival and replication. Among these effectors, there are several ubiquitin ligases and deubiquitinases (DUBs). We have been studying a family of L. pneumophila effectors named SidE that encodes for a group of DUBs. More recently, new data from our team showed that members of the SidE family such as SdeA, are not only DUBs but also ubiquitin ligases. Strikingly, the ubiquitin ligase activity of these proteins does not require the E1, E2 enzymes or ATP, which is unprecedented. Not only the reaction, but the type of linkage seems completely different as SdeA does not modify proteins by linking the C-terminus of ubiquitin to its substrates. This ubiquitination is not reversible by regular DUBs, but by another Legionella effector named SidJ, suggesting that the pathogen might tightly regulate this modification. Here, we propose to characterize the ubiquitination/deubiquitination catalyzed by SidEs. The results of this research have the potential to reveal a completely new mechanism of protein ubiquitination, which may have major impacts in the fields of cellular and molecular biology.
Project Details
Start Date
2018-10-01
End Date
2021-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Related Publications
Gan N., E.S. Nakayasu, P.J. Hollenbeck, and Z. Luo. 2019. "Legionella pneumophila inhibits immune signalling via MavC-mediated transglutaminase-induced ubiquitination of UBE2N." Nature Microbiology 4, no. 1:134-143. PNNL-SA-129705. doi:10.1038/s41564-018-0282-8
Gan N., H. Guan, Y. Huang, T. Yu, J. Fu, E.S. Nakayasu, and K. Puvar, et al. 2020. "Legionella pneumophilaregulates the activity of UBE2N by deamidase-mediated deubiquitination." The EMBO Journal 39, no. 4. PNNL-SA-141791. doi:10.15252/embj.2019102806
Gan N., Y. Liu, X. Zeng, J. Qiu, Y. Liu, C. He, and G.M. Fujimoto, et al. 2019. "Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase." Nature 572, no. 7769:387-391. PNNL-SA-142888. doi:10.1038/s41586-019-1439-1