Protein Complexes and Proteolytic Activation of the Cell Wall Hydrolase RipA Regulate Septal Resolution in Mycobacteria

PLoS Pathogens

Shoko Minami¹  Karen J. Kieser¹  Bree B. Aldridge¹  Eric J. Rubin¹  Michael C. Chao¹  Sarah M. Fortune¹  Tom Alber²  Daniela Mavrici² 

[1] Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America;Department of Molecular and Cell Biology, QB3 Institute, University of California-Berkeley, Berkeley, California, United States of America

关键词: Mycobacterium tuberculosis;    Hydrolases;    Peptidoglycans;    Cell walls;    Hyperexpression techniques;    Hydrolysis;    Cell cycle;    cell division;    Mycobacterium bovis;   

DOI  :  10.1371/journal.ppat.1003197

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Peptidoglycan hydrolases are a double-edged sword. They are required for normal cell division, but when dysregulated can become autolysins lethal to bacteria. How bacteria ensure that peptidoglycan hydrolases function only in the correct spatial and temporal context remains largely unknown. Here, we demonstrate that dysregulation converts the essential mycobacterial peptidoglycan hydrolase RipA to an autolysin that compromises cellular structural integrity. We find that mycobacteria control RipA activity through two interconnected levels of regulation in vivo—protein interactions coordinate PG hydrolysis, while proteolysis is necessary for RipA enzymatic activity. Dysregulation of RipA protein complexes by treatment with a peptidoglycan synthase inhibitor leads to excessive RipA activity and impairment of correct morphology. Furthermore, expression of a RipA dominant negative mutant or of differentially processed RipA homologues reveals that RipA is produced as a zymogen, requiring proteolytic processing for activity. The amount of RipA processing differs between fast-growing and slow-growing mycobacteria and correlates with the requirement for peptidoglycan hydrolase activity in these species. Together, the complex picture of RipA regulation is a part of a growing paradigm for careful control of cell wall hydrolysis by bacteria during growth, and may represent a novel target for chemotherapy development.

【 授权许可】

CC BY