Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production - Archive ouverte HAL Access content directly
Journal Articles The Journal of clinical investigation Year : 2023

Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production

Shyamala Thirunavukkarasu
  • Function : Author
Mushtaq Ahmed
Bruce A Rosa
Mark Boothby
Sung Hoon Cho
Javier Rangel-Moreno
Stanley K Mbandi
Ananya Gupta
  • Function : Author
Joaquin Zuniga
  • Function : Author
Makedonka Mitreva
  • Function : Author
Deepak Kaushal
Thomas J Scriba
Shabaana A Khader

Abstract

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.
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hal-04295605 , version 1 (23-11-2023)

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Shyamala Thirunavukkarasu, Mushtaq Ahmed, Bruce A Rosa, Mark Boothby, Sung Hoon Cho, et al.. Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production. The Journal of clinical investigation, 2023, 133 (12), ⟨10.1172/JCI158630⟩. ⟨hal-04295605⟩
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