Author: Li Jing
On the early morning of March 13, Nature published online via an accelerated article preview the latest research findings on the Gabija anti-phage system by the team of Prof. Wang Longfei from the School of Pharmaceutical Sciencesof Wuhan University, Taikang Center for Life and Medical Sciences of Wuhan University, and Zhongnan Hospital of Wuhan University Wuhan University. This paper is titled “Structures and activation mechanism of the Gabija anti-phage system”.
The Gabija system ranks as the third most prevalent prokaryotic immune system observed in nature, trailing only the restriction-modification system and the CRISPR system. Comprising only two genes, GajA and GajB, it stands out as one of the most versatile, effective, and simplified immune systems found demonstrating exceptional efficiency in conferring immunity against various virulent phages. GajA functions as a sequence-specific DNA endonuclease, subject to inhibition by ATP, while GajB acts as a UvrD-like helicase that utilizes ATP hydrolysis for energy. Two recent studies published in Nature have shed light on the structures and activation mechanism of the Gabija anti-phage system. Despite the significant attention drawn to its immune mechanism, the molecular intricacies underlying its anti-phage defense are not yet fully understood.
The study utilizes single-particle cryo-electron microscopy and biochemical techniques to capture, for the first time, both the activated state of GajA nuclease bound to DNA and the inhibited state bound to ATP, providing a comprehensive molecular-level elucidation of the mechanism of the Gabija system. In normal cellular physiology, the Gabija system is inhibited by ATP. However, upon bacterial infection by phages, the rapid replication of phages consumes a significant amount of ATP, relieving the inhibition of GajA by ATP. The TOPRIM domains at both ends of the GajA tetramer open up in opposite directions to facilitate DNA binding, causing DNA to bend near the cleavage site for efficient GajA cleavage. The nicked DNA can then activate the ATP hydrolysis activity of GajB, and the coordinated action of both enzymes ultimately leads to bacterial death and the abortive bacteriophage infection. Hence, the Gabija system potentially functions by recognizing metabolite depletion as a danger signal, constituting a distinctive prokaryotic immune mechanism. This investigation enhances our understanding of natural immune mechanisms and offers a novel avenue for investigating metabolites as potential danger signals for immune defense.
Prof. Wang Longfei from the School of Pharmaceutical Sciences, Wuhan University, and Prof. Zhu Bin from the College of Life Science and Technology, Huazhong University of Science and Technology, are the co-corresponding authors of the paper, while Li Jing, a Ph.D. student of the School of Pharmaceutical Sciences, Wuhan University, Cheng Rui, a postdoctoral fellow of the College of Life Science and Technology, Huazhong University of Science and Technology, and Wang Zhiming, an associate researcher of the School of Pharmaceutical Sciences, Wuhan University, are the co-first authors of the paper. Wuhan University is listed as the primary affiliation. The study has received substantial support from the cryo-electron microscopy unit of the Core Facility of Wuhan University. Senior engineer Li Danyang and technician Li Xiangning have also provided crucial assistance in data collection. The study has received funding support from multiple sources, including the National Key Research and Development Program, the startup funds of Wuhan University, the research funds of the Taikang Center for Life Science and Medical Sciences of Wuhan University, and the subsidy for large-scale instrumentation equipment of Wuhan University.
From left to right: Yuan Wuliu, Li Jing, Wang Longfei, Wang Zhiming, Xiao Jun
Prof. Wang Longfei’s team from the School of Pharmaceutical Sciences of Wuhan University has long been committed to research on immune system signaling pathways. The team has published numerous research articles in high-impact international journals such as Nature (2024, 2023), Science, Molecular Cell, and PNAS. Additionally, the team consistently recruits postdoctoral researchers specializing in biochemistry, structural biology, and immunology. Prospective doctoral researchers with relevant research backgrounds are welcome to join the team.
Link to papers: https://www.nature.com/articles/s41586-024-07270-x.
DOI：10.1038/s41586-024-07270-x
Rewritten by Teng Yumeng
Edited by Chen Aojie
