Mitochondrial Sirtuin TcSir2rp3 Affects TcSODA Activity and Oxidative Stress Response in Trypanosoma cruzi

Trypanosoma cruzi faces a variety of environmental scenarios during its life cycle, which include changes in the redox environment that requires a fine regulation of a complex antioxidant arsenal of enzymes. Reversible posttranslational modifications, as lysine acetylation, are a fast and economical...

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Autores principales:	Leila dos Santos Moura, Vinícius Santana Nunes, Antoniel A. S. Gomes, Ana Caroline de Castro Nascimento Sousa, Marcos R. M. Fontes, Sergio Schenkman, Nilmar Silvio Moretti
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Trypanosoma cruzi acetylation superoxide dismutase sirtuins oxidative stress Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/b2184ffb836c407d84b96031dc53e401
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spelling	oai:doaj.org-article:b2184ffb836c407d84b96031dc53e4012021-11-11T07:45:55ZMitochondrial Sirtuin TcSir2rp3 Affects TcSODA Activity and Oxidative Stress Response in Trypanosoma cruzi2235-298810.3389/fcimb.2021.773410https://doaj.org/article/b2184ffb836c407d84b96031dc53e4012021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcimb.2021.773410/fullhttps://doaj.org/toc/2235-2988Trypanosoma cruzi faces a variety of environmental scenarios during its life cycle, which include changes in the redox environment that requires a fine regulation of a complex antioxidant arsenal of enzymes. Reversible posttranslational modifications, as lysine acetylation, are a fast and economical way for cells to react to environmental conditions. Recently, we found that the main antioxidant enzymes, including the mitochondrial superoxide dismutase A (TcSODA) are acetylated in T. cruzi, suggesting that protein acetylation could participate in the oxidative stress response in T. cruzi. Therefore, we investigated whether mitochondrial lysine deacetylase TcSir2rp3 was involved in the activity control of TcSODA. We observed an increased resistance to hydrogen peroxide and menadione in parasites overexpressing TcSir2rp3. Increased resistance was also found for benznidazole and nifurtimox, known to induce reactive oxidative and nitrosactive species in the parasite, associated to that a reduction in the ROS levels was observed. To better understand the way TcSir2rp3 could contributes to oxidative stress response, we analyzed the expression of TcSODA in the TcSir2rp3 overexpressing parasites and did not detect any increase in protein levels of this enzyme. However, we found that these parasites presented higher levels of superoxide dismutase activity, and also that TcSir2rp3 and TcSODA interacts in vivo. Knowing that TcSODA is acetylated at lysine residues K44 and K97, and that K97 is located at a similar region in the protein structure as K68 in human manganese superoxide dismutase (MnSOD), responsible for regulating MnSOD activity, we generated mutated versions of TcSODA at K44 and K97 and found that replacing K97 by glutamine, which mimics an acetylated lysine, negatively affects the enzyme activity in vitro. By using molecular dynamics approaches, we revealed that acetylation of K97 induces specific conformational changes in TcSODA with respect to hydrogen-bonding pattern to neighbor residues, suggesting a key participation of this residue to modulate the affinity to O2−. Taken together, our results showed for the first time the involvement of lysine acetylation in the maintenance of homeostatic redox state in trypanosomatids, contributing to the understanding of mechanisms used by T. cruzi to progress during the infection.Leila dos Santos MouraLeila dos Santos MouraVinícius Santana NunesAntoniel A. S. GomesAna Caroline de Castro Nascimento SousaAna Caroline de Castro Nascimento SousaMarcos R. M. FontesSergio SchenkmanNilmar Silvio MorettiNilmar Silvio MorettiFrontiers Media S.A.articleTrypanosoma cruziacetylationsuperoxide dismutasesirtuinsoxidative stressMicrobiologyQR1-502ENFrontiers in Cellular and Infection Microbiology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Trypanosoma cruzi acetylation superoxide dismutase sirtuins oxidative stress Microbiology QR1-502
spellingShingle	Trypanosoma cruzi acetylation superoxide dismutase sirtuins oxidative stress Microbiology QR1-502 Leila dos Santos Moura Leila dos Santos Moura Vinícius Santana Nunes Antoniel A. S. Gomes Ana Caroline de Castro Nascimento Sousa Ana Caroline de Castro Nascimento Sousa Marcos R. M. Fontes Sergio Schenkman Nilmar Silvio Moretti Nilmar Silvio Moretti Mitochondrial Sirtuin TcSir2rp3 Affects TcSODA Activity and Oxidative Stress Response in Trypanosoma cruzi
description	Trypanosoma cruzi faces a variety of environmental scenarios during its life cycle, which include changes in the redox environment that requires a fine regulation of a complex antioxidant arsenal of enzymes. Reversible posttranslational modifications, as lysine acetylation, are a fast and economical way for cells to react to environmental conditions. Recently, we found that the main antioxidant enzymes, including the mitochondrial superoxide dismutase A (TcSODA) are acetylated in T. cruzi, suggesting that protein acetylation could participate in the oxidative stress response in T. cruzi. Therefore, we investigated whether mitochondrial lysine deacetylase TcSir2rp3 was involved in the activity control of TcSODA. We observed an increased resistance to hydrogen peroxide and menadione in parasites overexpressing TcSir2rp3. Increased resistance was also found for benznidazole and nifurtimox, known to induce reactive oxidative and nitrosactive species in the parasite, associated to that a reduction in the ROS levels was observed. To better understand the way TcSir2rp3 could contributes to oxidative stress response, we analyzed the expression of TcSODA in the TcSir2rp3 overexpressing parasites and did not detect any increase in protein levels of this enzyme. However, we found that these parasites presented higher levels of superoxide dismutase activity, and also that TcSir2rp3 and TcSODA interacts in vivo. Knowing that TcSODA is acetylated at lysine residues K44 and K97, and that K97 is located at a similar region in the protein structure as K68 in human manganese superoxide dismutase (MnSOD), responsible for regulating MnSOD activity, we generated mutated versions of TcSODA at K44 and K97 and found that replacing K97 by glutamine, which mimics an acetylated lysine, negatively affects the enzyme activity in vitro. By using molecular dynamics approaches, we revealed that acetylation of K97 induces specific conformational changes in TcSODA with respect to hydrogen-bonding pattern to neighbor residues, suggesting a key participation of this residue to modulate the affinity to O2−. Taken together, our results showed for the first time the involvement of lysine acetylation in the maintenance of homeostatic redox state in trypanosomatids, contributing to the understanding of mechanisms used by T. cruzi to progress during the infection.
format	article
author	Leila dos Santos Moura Leila dos Santos Moura Vinícius Santana Nunes Antoniel A. S. Gomes Ana Caroline de Castro Nascimento Sousa Ana Caroline de Castro Nascimento Sousa Marcos R. M. Fontes Sergio Schenkman Nilmar Silvio Moretti Nilmar Silvio Moretti
author_facet	Leila dos Santos Moura Leila dos Santos Moura Vinícius Santana Nunes Antoniel A. S. Gomes Ana Caroline de Castro Nascimento Sousa Ana Caroline de Castro Nascimento Sousa Marcos R. M. Fontes Sergio Schenkman Nilmar Silvio Moretti Nilmar Silvio Moretti
author_sort	Leila dos Santos Moura
title	Mitochondrial Sirtuin TcSir2rp3 Affects TcSODA Activity and Oxidative Stress Response in Trypanosoma cruzi
title_short	Mitochondrial Sirtuin TcSir2rp3 Affects TcSODA Activity and Oxidative Stress Response in Trypanosoma cruzi
title_full	Mitochondrial Sirtuin TcSir2rp3 Affects TcSODA Activity and Oxidative Stress Response in Trypanosoma cruzi
title_fullStr	Mitochondrial Sirtuin TcSir2rp3 Affects TcSODA Activity and Oxidative Stress Response in Trypanosoma cruzi
title_full_unstemmed	Mitochondrial Sirtuin TcSir2rp3 Affects TcSODA Activity and Oxidative Stress Response in Trypanosoma cruzi
title_sort	mitochondrial sirtuin tcsir2rp3 affects tcsoda activity and oxidative stress response in trypanosoma cruzi
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/b2184ffb836c407d84b96031dc53e401
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Mitochondrial Sirtuin TcSir2rp3 Affects TcSODA Activity and Oxidative Stress Response in Trypanosoma cruzi

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