Abstract
Mycobacterium tuberculosis, the causative agent of tuberculosis, withstands diverse environmental stresses in the host. The periplasmic protease HtrA is required only to survive extreme conditions in most bacteria but is predicted to be essential for normal growth in mycobacteria. We confirm that HtrA is indeed essential in Mycobacterium smegmatis and interacts with another essential protein of unknown function, LppZ. However, the loss of any of three unlinked genes, including those encoding Ami3, a peptidoglycan muramidase, and Pmt, a mannosyltransferase, suppresses the essentiality of both HtrA and LppZ, indicating the functional relevance of these genes' protein products. Our data indicate that HtrA-LppZ is required to counteract the accumulation of active Ami3, which is toxic under the stabilizing influence of Pmt-based mannosylation. This suggests that HtrA-LppZ blocks the toxicity of a cell wall enzyme to maintain mycobacterial homeostasis.