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Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production
The ADP ribosyltransferases (PARPs 1–17) regulate diverse cellular processes, including DNA damage repair. PARPs are classified on the basis of their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). Although PARP9 mRNA expression is significantly increase...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10266794/ https://www.ncbi.nlm.nih.gov/pubmed/37200107 http://dx.doi.org/10.1172/JCI158630 |
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author | Thirunavukkarasu, Shyamala Ahmed, Mushtaq Rosa, Bruce A. Boothby, Mark Cho, Sung Hoon Rangel-Moreno, Javier Mbandi, Stanley K. Schreiber, Valérie Gupta, Ananya Zuniga, Joaquin Mitreva, Makedonka Kaushal, Deepak Scriba, Thomas J. Khader, Shabaana A. |
author_facet | Thirunavukkarasu, Shyamala Ahmed, Mushtaq Rosa, Bruce A. Boothby, Mark Cho, Sung Hoon Rangel-Moreno, Javier Mbandi, Stanley K. Schreiber, Valérie Gupta, Ananya Zuniga, Joaquin Mitreva, Makedonka Kaushal, Deepak Scriba, Thomas J. Khader, Shabaana A. |
author_sort | Thirunavukkarasu, Shyamala |
collection | PubMed |
description | The ADP ribosyltransferases (PARPs 1–17) regulate diverse cellular processes, including DNA damage repair. PARPs are classified on the basis of their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). Although PARP9 mRNA expression is significantly increased in progressive tuberculosis (TB) in humans, its participation in host immunity to TB is unknown. Here, we show that PARP9 mRNA encoding the MARylating PARP9 enzyme was upregulated during TB in humans and mice and provide evidence of a critical modulatory role for PARP9 in DNA damage, cyclic GMP–AMP synthase (cGAS) expression, and type I IFN production during TB. Thus, Parp9-deficient mice were susceptible to Mycobacterium tuberculosis infection and exhibited increased TB disease, cGAS and 2′3′-cyclic GMP-AMP (cGAMP) expression, and type I IFN production, along with upregulation of complement and coagulation pathways. Enhanced M. tuberculosis susceptibility is type I IFN dependent, as blockade of IFN α receptor (IFNAR) signaling reversed the enhanced susceptibility of Parp9(–/–) mice. Thus, in sharp contrast to PARP9 enhancement of type I IFN production in viral infections, this member of the MAR family plays a protective role by limiting type I IFN responses during TB. |
format | Online Article Text |
id | pubmed-10266794 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-102667942023-06-15 Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production Thirunavukkarasu, Shyamala Ahmed, Mushtaq Rosa, Bruce A. Boothby, Mark Cho, Sung Hoon Rangel-Moreno, Javier Mbandi, Stanley K. Schreiber, Valérie Gupta, Ananya Zuniga, Joaquin Mitreva, Makedonka Kaushal, Deepak Scriba, Thomas J. Khader, Shabaana A. J Clin Invest Research Article The ADP ribosyltransferases (PARPs 1–17) regulate diverse cellular processes, including DNA damage repair. PARPs are classified on the basis of their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). Although PARP9 mRNA expression is significantly increased in progressive tuberculosis (TB) in humans, its participation in host immunity to TB is unknown. Here, we show that PARP9 mRNA encoding the MARylating PARP9 enzyme was upregulated during TB in humans and mice and provide evidence of a critical modulatory role for PARP9 in DNA damage, cyclic GMP–AMP synthase (cGAS) expression, and type I IFN production during TB. Thus, Parp9-deficient mice were susceptible to Mycobacterium tuberculosis infection and exhibited increased TB disease, cGAS and 2′3′-cyclic GMP-AMP (cGAMP) expression, and type I IFN production, along with upregulation of complement and coagulation pathways. Enhanced M. tuberculosis susceptibility is type I IFN dependent, as blockade of IFN α receptor (IFNAR) signaling reversed the enhanced susceptibility of Parp9(–/–) mice. Thus, in sharp contrast to PARP9 enhancement of type I IFN production in viral infections, this member of the MAR family plays a protective role by limiting type I IFN responses during TB. American Society for Clinical Investigation 2023-06-15 /pmc/articles/PMC10266794/ /pubmed/37200107 http://dx.doi.org/10.1172/JCI158630 Text en © 2023 Thirunavukkarasu et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Thirunavukkarasu, Shyamala Ahmed, Mushtaq Rosa, Bruce A. Boothby, Mark Cho, Sung Hoon Rangel-Moreno, Javier Mbandi, Stanley K. Schreiber, Valérie Gupta, Ananya Zuniga, Joaquin Mitreva, Makedonka Kaushal, Deepak Scriba, Thomas J. Khader, Shabaana A. Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production |
title | Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production |
title_full | Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production |
title_fullStr | Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production |
title_full_unstemmed | Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production |
title_short | Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production |
title_sort | poly(adp-ribose) polymerase 9 mediates early protection against mycobacterium tuberculosis infection by regulating type i ifn production |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10266794/ https://www.ncbi.nlm.nih.gov/pubmed/37200107 http://dx.doi.org/10.1172/JCI158630 |
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