The National Facility for Protein Science in Shanghai (NFPSS), a major national scientific infrastructure project established under China's 11th Five-Year Plan and the world's first comprehensive large-scale facility in life sciences, supported research recognized among "China's Top 10 Medical Science Advances of 2020" by Health News. The award-winning study "Immune Evasion Mechanism of Tuberculosis Bacteria Revealed" was conducted by the team of Professor Ge Baoxue from Shanghai Pulmonary Hospital affiliated with Tongji University in collaboration with Academician Zihe Rao's team from ShanghaiTech University.
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a top-ten cause of death globally. Understanding Mtb's pathogenesis is crucial for disease control. This study employed an innovative function-based screening approach to identify a novel Mtb effector protein Rv0222, confirming its role in suppressing host inflammatory responses. The research established an effective screening methodology for studying Mtb immune mechanisms. The study revealed that the critical virulence factor Rv0222, a secretory protein of Mtb, requires host-mediated K11-linked polyubiquitination at lysine-76 (K76) to recruit anti-inflammatory proteins. This process blocks host anti-tuberculosis immune pathways, enabling bacterial immune evasion and disease progression.
After identifying the novel effector protein Rv0222,the research team utilized NFPSS's Protein Complex Crystallography Station BL19U1 to determine the high-resolution crystal structure of this protein (PDB ID: 6LDZ). Through structural and functional analysis,they precisely identified that K11-linked polyubiquitination at K76 activates Rv0222's virulence function,providing an accurate target for novel anti-tuberculosis drug development.
The study centered on the fundamental principle that host-pathogen interactions underlie infectious diseases,investigating structural and functional mechanisms of key pathogenic and host molecular machinery during Mtb infection. This research comprehensively elucidated how Mtb exploits host components for immune evasion,expanded scientific understanding of ubiquitination systems in infectious disease regulation,and pioneered novel anti-tuberculosis drug development targeting host-pathogen interactions.
https://doi.org/10.1038/s41586-019-1915-7
