Abstract
Innate immune cells are critical in protective immunity against viral infections, involved in sensing foreign viral nucleic acids. Here we report that the poly(ADP-ribose) polymerase 9 (PARP9), a member of PARP family, serves as a non-canonical sensor for RNA virus to initiate and amplify type I interferon (IFN) production. We find knockdown or deletion of PARP9 in human or mouse dendritic cells and macrophages inhibits type I IFN production in response to double strand RNA stimulation or RNA virus infection. Furthermore, mice deficient for PARP9 show enhanced susceptibility to infections with RNA viruses because of the impaired type I IFN production. Mechanistically, we show that PARP9 recognizes and binds viral RNA, with resultant recruitment and activation of the phosphoinositide 3-kinase (PI3K) and AKT3 pathway, independent of mitochondrial antiviral-signaling (MAVS). PI3K/AKT3 then activates the IRF3 and IRF7 by phosphorylating IRF3 at Ser385 and IRF7 at Ser437/438 mediating type I IFN production. Together, we reveal a critical role for PARP9 as a non-canonical RNA sensor that depends on the PI3K/AKT3 pathway to produce type I IFN. These findings may have important clinical implications in controlling viral infections and viral-induced diseases by targeting PARP9.
Highlights
Innate immune cells are the first line of defense against invading pathogens including viruses through multiple mechanisms
The kinetics of LPIC-induced IFN-β showed IFN-β reached highest level in control and poly(ADP-ribose) polymerase 9 (PARP9) knockdown human monocyte-derived dendritic cells (MDDC) at 24 h after LPIC stimulation and the difference was the most significant (Fig. 1m). These data suggested that human PARP9 mediated the type I IFN production in human innate immune cells including macrophages and dendritic cells (DCs) in response to dsRNA stimulation and RNA virus infection
Since PARP9 expression was low in mitochondrial antiviral-signaling (MAVS) KO bone marrowderived dendritic cells (BMDC) and there were few type I IFN induction in MAVS KO BMDC after RNA virus infection, we further investigated if induced PARP9 could induce MAVSindependent more type I IFN production in MAVS KO BMDC after twice challenge with RNA viruses
Summary
Innate immune cells are the first line of defense against invading pathogens including viruses through multiple mechanisms. For sensing the virus-derived nucleic acids in the cytosol, many PRRs have been identified, such as viral RNA sensors RIG-I like receptors (RLRs), viral DNA sensors cGAS (cyclic GMP-AMP synthase), IFI16 (IFN gamma-inducible protein 16), DAI (DNA-dependent activator of IFN-regulatory factors), DDX41 and many others[2]. Activation and oligomerization into a prion-like aggregate, which activates the TBK1 and IKK kinases This culminates in the activation of transcription factors NF-κB, IRF3, and IRF7, which translocate to the nucleus to induce type I IFN and other antiviral genes[7]. Whether other cytosolic RNA sensors in innate immune cells can trigger MAVS-independent type I IFN production pathway remains largely unknown. We found that PARP9 was highly induced by IFN-α in dendritic cells (DCs) and played an essential role in producing type I IFN by serving as a MAVS-independent RNA sensor during RNA virus infection. Our study identified PARP9 as a non-canonical RNA sensor for RNA viruses, and delineated an unknown function for PARP family proteins in antiviral immunity in DCs
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