mRNA Degradation Rates Are Coupled to Metabolic Status in <named-content content-type="genus-species">Mycobacterium smegmatis</named-content>

ABSTRACT The success of Mycobacterium tuberculosis as a human pathogen is due in part to its ability to survive stress conditions, such as hypoxia or nutrient deprivation, by entering nongrowing states. In these low-metabolism states, M. tuberculosis can tolerate antibiotics and develop genetically...

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Autores principales:	Diego A. Vargas-Blanco, Ying Zhou, L. Gregory Zamalloa, Tim Antonelli, Scarlet S. Shell
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	ATP Mycobacterium smegmatis carbon starvation hypoxia mRNA degradation mRNA stability Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9b42c797fea84faf9dd2fa0b2e9d2c18
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spelling	oai:doaj.org-article:9b42c797fea84faf9dd2fa0b2e9d2c182021-11-15T16:22:10ZmRNA Degradation Rates Are Coupled to Metabolic Status in <named-content content-type="genus-species">Mycobacterium smegmatis</named-content>10.1128/mBio.00957-192150-7511https://doaj.org/article/9b42c797fea84faf9dd2fa0b2e9d2c182019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00957-19https://doaj.org/toc/2150-7511ABSTRACT The success of Mycobacterium tuberculosis as a human pathogen is due in part to its ability to survive stress conditions, such as hypoxia or nutrient deprivation, by entering nongrowing states. In these low-metabolism states, M. tuberculosis can tolerate antibiotics and develop genetically encoded antibiotic resistance, making its metabolic adaptation to stress crucial for survival. Numerous bacteria, including M. tuberculosis, have been shown to reduce their rates of mRNA degradation under growth limitation and stress. While the existence of this response appears to be conserved across species, the underlying bacterial mRNA stabilization mechanisms remain unknown. To better understand the biology of nongrowing mycobacteria, we sought to identify the mechanistic basis of mRNA stabilization in the nonpathogenic model Mycobacterium smegmatis. We found that mRNA half-life was responsive to energy stress, with carbon starvation and hypoxia causing global mRNA stabilization. This global stabilization was rapidly reversed when hypoxia-adapted cultures were reexposed to oxygen, even in the absence of new transcription. The stringent response and RNase levels did not explain mRNA stabilization, nor did transcript abundance. This led us to hypothesize that metabolic changes during growth cessation impact the activities of degradation proteins, increasing mRNA stability. Indeed, bedaquiline and isoniazid, two drugs with opposing effects on cellular energy status, had opposite effects on mRNA half-lives in growth-arrested cells. Taken together, our results indicate that mRNA stability in mycobacteria is not directly regulated by growth status but rather is dependent on the status of energy metabolism. IMPORTANCE The logistics of tuberculosis therapy are difficult, requiring multiple drugs for many months. Mycobacterium tuberculosis survives in part by entering nongrowing states in which it is metabolically less active and thus less susceptible to antibiotics. Basic knowledge on how M. tuberculosis survives during these low-metabolism states is incomplete, and we hypothesize that optimized energy resource management is important. Here, we report that slowed mRNA turnover is a common feature of mycobacteria under energy stress but is not dependent on the mechanisms that have generally been postulated in the literature. Finally, we found that mRNA stability and growth status can be decoupled by a drug that causes growth arrest but increases metabolic activity, indicating that mRNA stability responds to metabolic status rather than to growth rate per se. Our findings suggest a need to reorient studies of global mRNA stabilization to identify novel mechanisms that are presumably responsible.Diego A. Vargas-BlancoYing ZhouL. Gregory ZamalloaTim AntonelliScarlet S. ShellAmerican Society for MicrobiologyarticleATPMycobacterium smegmatiscarbon starvationhypoxiamRNA degradationmRNA stabilityMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	ATP Mycobacterium smegmatis carbon starvation hypoxia mRNA degradation mRNA stability Microbiology QR1-502
spellingShingle	ATP Mycobacterium smegmatis carbon starvation hypoxia mRNA degradation mRNA stability Microbiology QR1-502 Diego A. Vargas-Blanco Ying Zhou L. Gregory Zamalloa Tim Antonelli Scarlet S. Shell mRNA Degradation Rates Are Coupled to Metabolic Status in <named-content content-type="genus-species">Mycobacterium smegmatis</named-content>
description	ABSTRACT The success of Mycobacterium tuberculosis as a human pathogen is due in part to its ability to survive stress conditions, such as hypoxia or nutrient deprivation, by entering nongrowing states. In these low-metabolism states, M. tuberculosis can tolerate antibiotics and develop genetically encoded antibiotic resistance, making its metabolic adaptation to stress crucial for survival. Numerous bacteria, including M. tuberculosis, have been shown to reduce their rates of mRNA degradation under growth limitation and stress. While the existence of this response appears to be conserved across species, the underlying bacterial mRNA stabilization mechanisms remain unknown. To better understand the biology of nongrowing mycobacteria, we sought to identify the mechanistic basis of mRNA stabilization in the nonpathogenic model Mycobacterium smegmatis. We found that mRNA half-life was responsive to energy stress, with carbon starvation and hypoxia causing global mRNA stabilization. This global stabilization was rapidly reversed when hypoxia-adapted cultures were reexposed to oxygen, even in the absence of new transcription. The stringent response and RNase levels did not explain mRNA stabilization, nor did transcript abundance. This led us to hypothesize that metabolic changes during growth cessation impact the activities of degradation proteins, increasing mRNA stability. Indeed, bedaquiline and isoniazid, two drugs with opposing effects on cellular energy status, had opposite effects on mRNA half-lives in growth-arrested cells. Taken together, our results indicate that mRNA stability in mycobacteria is not directly regulated by growth status but rather is dependent on the status of energy metabolism. IMPORTANCE The logistics of tuberculosis therapy are difficult, requiring multiple drugs for many months. Mycobacterium tuberculosis survives in part by entering nongrowing states in which it is metabolically less active and thus less susceptible to antibiotics. Basic knowledge on how M. tuberculosis survives during these low-metabolism states is incomplete, and we hypothesize that optimized energy resource management is important. Here, we report that slowed mRNA turnover is a common feature of mycobacteria under energy stress but is not dependent on the mechanisms that have generally been postulated in the literature. Finally, we found that mRNA stability and growth status can be decoupled by a drug that causes growth arrest but increases metabolic activity, indicating that mRNA stability responds to metabolic status rather than to growth rate per se. Our findings suggest a need to reorient studies of global mRNA stabilization to identify novel mechanisms that are presumably responsible.
format	article
author	Diego A. Vargas-Blanco Ying Zhou L. Gregory Zamalloa Tim Antonelli Scarlet S. Shell
author_facet	Diego A. Vargas-Blanco Ying Zhou L. Gregory Zamalloa Tim Antonelli Scarlet S. Shell
author_sort	Diego A. Vargas-Blanco
title	mRNA Degradation Rates Are Coupled to Metabolic Status in <named-content content-type="genus-species">Mycobacterium smegmatis</named-content>
title_short	mRNA Degradation Rates Are Coupled to Metabolic Status in <named-content content-type="genus-species">Mycobacterium smegmatis</named-content>
title_full	mRNA Degradation Rates Are Coupled to Metabolic Status in <named-content content-type="genus-species">Mycobacterium smegmatis</named-content>
title_fullStr	mRNA Degradation Rates Are Coupled to Metabolic Status in <named-content content-type="genus-species">Mycobacterium smegmatis</named-content>
title_full_unstemmed	mRNA Degradation Rates Are Coupled to Metabolic Status in <named-content content-type="genus-species">Mycobacterium smegmatis</named-content>
title_sort	mrna degradation rates are coupled to metabolic status in <named-content content-type="genus-species">mycobacterium smegmatis</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/9b42c797fea84faf9dd2fa0b2e9d2c18
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mRNA Degradation Rates Are Coupled to Metabolic Status in <named-content content-type="genus-species">Mycobacterium smegmatis</named-content>

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