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A conserved translation factor is required for optimal synthesis of a membrane protein family in mycobacteria

By Skye R.S. Fishbein, Ian D Wolf, Charles L. Dulberger, Albert Wang, Hasmik Keshishian, Luke Wallace, Steven A Carr, Thomas R. Ioerger, E. Hesper Rego, Eric J. Rubin

Posted 11 Dec 2019
bioRxiv DOI: 10.1101/872341

Ribosomes require the activity of associated GTPases to synthesize proteins. Despite strong evolutionary conservation, the roles of many of these remain unknown. For example, LepA (also known as elongation factor 4) is a ribosome-associated GTPase found in bacteria, mitochondria, and chloroplasts, yet its physiological contribution to cell survival is not clear. Recently, we found that loss of lepA in Mycobacterium smegmatis (Msm) altered tolerance to rifampin, a drug that targets a non-ribosomal cellular process. To uncover the determinants of LepA-mediated drug tolerance, we characterized the whole-cell proteomes and transcriptomes of a lepA deletion mutant relative to a wild-type strain. We find that LepA is important for the steady-state abundance of an outer membrane porin, which is integral to nutrient uptake and drug susceptibility. Loss of LepA leads to decreased amount of porin in the membrane, resulting in the drug tolerance phenotype of the lepA mutant. LepA control requires a sequence motif in the 5' region of the porin transcript. Thus, LepA controls the abundance of specific proteins, likely through its activity during translation.

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