scholarly journals Identification of poly(ADP-ribose) polymerase 9 (PARP9) as a noncanonical sensor for RNA virus in dendritic cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Junji Xing ◽  
Ao Zhang ◽  
Yong Du ◽  
Mingli Fang ◽  
Laurie J. Minze ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Protective Immunity ◽  
Viral Infections ◽  
Rna Virus ◽  
Critical Role ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Mitochondrial Antiviral Signaling ◽  
Phosphoinositide 3 Kinase

AbstractInnate 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.

scholarly journals Cutting Edge: Critical Role of IκB Kinase α in TLR7/9-Induced Type I IFN Production by Conventional Dendritic Cells

2010 ◽  
Vol 184 (7) ◽  
pp. 3341-3345 ◽  
Author(s):  
Katsuaki Hoshino ◽  
Izumi Sasaki ◽  
Takahiro Sugiyama ◽  
Takahiro Yano ◽  
Chihiro Yamazaki ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Critical Role ◽  
Cutting Edge ◽  
Type I ◽  
Type I Ifn ◽  
Iκb Kinase

scholarly journals TLR7 stimulation in human plasmacytoid dendritic cells leads to the induction of early IFN-inducible genes in the absence of type I IFN

Blood ◽  
2009 ◽  
Vol 114 (9) ◽  
pp. 1794-1802 ◽  
Author(s):  
Jérémy Di Domizio ◽  
Ariane Blum ◽  
Maighread Gallagher-Gambarelli ◽  
Jean-Paul Molens ◽  
Laurence Chaperot ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Plasmacytoid Dendritic Cells ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
P38mapk Pathway ◽  
Inducible Genes ◽  
Level Production ◽  
Early Phases ◽  
Tlr7 Stimulation

On recognition of influenza virus (Flu) by TLR7, plasmacytoid dendritic cells (pDCs) produce type I IFN in significant amounts. Synthetic TLR7 ligands induce the maturation of pDCs, as evidenced by the expression of costimulatory molecules and the production of proinflammatory cytokines; however, they induce only low-level production of IFN-α. To dissect the TLR7 signaling in pDCs and how these different profiles are induced, we studied the effects of 2 TLR7 ligands (Flu and CL097) on the activation of blood-isolated pDCs and the human GEN2.2 pDC cell line. Type I IFN production by pDCs correlates with differential interferon regulatory factor 7 (IRF7) translocation into the nucleus induced by the 2 TLR7 ligands. Surprisingly, with both activators we nevertheless observed the rapid expression of the IFN-inducible genes mxa, cxcl10, and trail within 4 hours of stimulation. This expression, controlled by STAT1 phosphorylation, was independent of type I IFN. STAT1 activation was found to be strictly dependent on the PI3K-p38MAPK pathway, showing a new signaling pathway leading to rapid expression of IFN-inducible genes after TLR7 triggering. Thus, pDCs, through this unusual TLR7 signaling, have the capacity to promptly respond to viral infection during the early phases of the innate immune response.

scholarly journals IFN-β signalling regulates RAW 264.7 macrophage activation, cytokine production, and killing activity

2019 ◽  
Vol 26 (3) ◽  
pp. 172-182
Author(s):  
Yalda Karimi ◽  
Elizabeth C Giles ◽  
Fatemeh Vahedi ◽  
Marianne V Chew ◽  
Tina Nham ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Critical Role ◽  
Raw 264.7 ◽  
Type I ◽  
Type I Ifn ◽  
Killing Activity ◽  
Raw 264.7 Macrophage

Type I IFN holds a critical role in host defence, providing protection against pathogenic organisms through coordinating a pro-inflammatory response. Type I IFN provides additional protection through mitigating this inflammatory response, preventing immunopathology. Within the context of viral infections, type I IFN signalling commonly results in successful viral clearance. Conversely, during bacterial infections, the role of type I IFN is less predictable, leading to either detrimental or beneficial outcomes. The factors responsible for the variability in the role of type I IFN remain unclear. Here, we aimed to elucidate differences in the effect of type I IFN signalling on macrophage functioning in the context of TLR activation. Using RAW 264.7 macrophages, we observed the influence of type I IFN to be dependent on the type of TLR ligand, length of TLR exposure and the timing of IFN-β signalling. However, in all conditions, IFN-β increased the production of the anti-inflammatory cytokine IL-10. Examination of RAW 264.7 macrophage function showed type I IFN to induce an activated phenotype by up-regulating MHC II expression and enhancing killing activity. Our results support a context-dependent role for type I IFN in regulating RAW 264.7 macrophage activity.

scholarly journals Alphaherpesvirus-induced activation of plasmacytoid dendritic cells depends on the viral glycoprotein gD and is inhibited by non-infectious light particles

2021 ◽  
Vol 17 (11) ◽  
pp. e1010117
Author(s):  
Jonas L. Delva ◽  
Cliff Van Waesberghe ◽  
Barbara G. Klupp ◽  
Thomas C. Mettenleiter ◽  
Herman W. Favoreel
Keyword(s):  
Dendritic Cells ◽  
Pseudorabies Virus ◽  
Viral Infections ◽  
Critical Role ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Viral Glycoprotein ◽  
Dna Viruses ◽  
Endosomal Acidification ◽  
Simplex Virus

Plasmacytoid dendritic cells (pDC) are important innate immune cells during the onset of viral infections as they are specialized in the production of massive amounts of antiviral type I interferon (IFN). Alphaherpesviruses such as herpes simplex virus (HSV) or pseudorabies virus (PRV) are double stranded DNA viruses and potent stimulators of pDC. Detailed information on how PRV activates porcine pDC is lacking. Using PRV and porcine primary pDC, we report here that PRV virions, so-called heavy (H-)particles, trigger IFNα production by pDC, whereas light (L-) particles that lack viral DNA and capsid do not. Activation of pDC requires endosomal acidification and, importantly, depends on the PRV gD envelope glycoprotein and O-glycosylations. Intriguingly, both for PRV and HSV-1, we found that L-particles suppress H-particle-mediated activation of pDC, a process which again depends on viral gD. This is the first report describing that gD plays a critical role in alphaherpesvirus-induced pDC activation and that L-particles directly interfere with alphaherpesvirus-induced IFNα production by pDC.

scholarly journals Control of antiviral innate immune response by protein geranylgeranylation

2019 ◽  
Vol 5 (5) ◽  
pp. eaav7999 ◽  
Author(s):  
Shigao Yang ◽  
Alfred T. Harding ◽  
Catherine Sweeney ◽  
David Miao ◽  
Gregory Swan ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Innate Immune Response ◽  
Influenza A ◽  
Rna Virus ◽  
Critical Role ◽  
Innate Immune ◽  
Junction Protein ◽  
Mitochondrial Antiviral Signaling ◽  
Destructive Inflammation

The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS’ interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIPL to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.

scholarly journals Phospholipase A2 inhibitor and LY6/PLAUR domain-containing protein PINLYP regulates type I interferon innate immunity

2021 ◽  
Vol 119 (1) ◽  
pp. e2111115119
Author(s):  
Zhongshun Liu ◽  
Congwei Jiang ◽  
Zhangmengxue Lei ◽  
Sihan Dong ◽  
Linlin Kuang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Dendritic Cells ◽  
Phospholipase A2 ◽  
Rna Virus ◽  
Cell Types ◽  
Type I Interferons ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Phospholipase A2 Inhibitor

Type I interferons (IFNs) are the first frontline of the host innate immune response against invading pathogens. Herein, we characterized an unknown protein encoded by phospholipase A2 inhibitor and LY6/PLAUR domain-containing (PINLYP) gene that interacted with TBK1 and induced type I IFN in a TBK1- and IRF3-dependent manner. Loss of PINLYP impaired the activation of IRF3 and production of IFN-β induced by DNA virus, RNA virus, and various Toll-like receptor ligands in multiple cell types. Because PINLYP deficiency in mice engendered an early embryonic lethality in mice, we generated a conditional mouse in which PINLYP was depleted in dendritic cells. Mice lacking PINLYP in dendritic cells were defective in type I IFN induction and more susceptible to lethal virus infection. Thus, PINLYP is a positive regulator of type I IFN innate immunity and important for effective host defense against viral infection.

scholarly journals Cellular nucleic acid–binding protein is essential for type I interferon–mediated immunity to RNA virus infection

2021 ◽  
Vol 118 (26) ◽  
pp. e2100383118
Author(s):  
Yongzhi Chen ◽  
Xuqiu Lei ◽  
Zhaozhao Jiang ◽  
Katherine A. Fitzgerald
Keyword(s):  
Gene Expression ◽  
Nucleic Acid ◽  
Virus Infection ◽  
Rna Virus ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Nucleic Acid Binding ◽  
Nucleic Acid Binding Protein ◽  
Acid Binding Protein

Type I interferons (IFNs) are innate immune cytokines required to establish cellular host defense. Precise control of IFN gene expression is crucial to maintaining immune homeostasis. Here, we demonstrated that cellular nucleic acid–binding protein (CNBP) was required for the production of type I IFNs in response to RNA virus infection. CNBP deficiency markedly impaired IFN production in macrophages and dendritic cells that were infected with a panel of RNA viruses or stimulated with synthetic double-stranded RNA. Furthermore, CNBP-deficient mice were more susceptible to influenza virus infection than were wild-type mice. Mechanistically, CNBP was phosphorylated and translocated to the nucleus, where it directly binds to the promoter of IFNb in response to RNA virus infection. Furthermore, CNBP controlled the recruitment of IFN regulatory factor (IRF) 3 and IRF7 to IFN promoters for the maximal induction of IFNb gene expression. These studies reveal a previously unrecognized role for CNBP as a transcriptional regulator of type I IFN genes engaged downstream of RNA virus–mediated innate immune signaling, which provides an additional layer of control for IRF3- and IRF7-dependent type I IFN gene expression and the antiviral innate immune response.

scholarly journals A type I IFN–Flt3 ligand axis augments plasmacytoid dendritic cell development from common lymphoid progenitors

2013 ◽  
Vol 210 (12) ◽  
pp. 2515-2522 ◽  
Author(s):  
Yi-Ling Chen ◽  
Ting-Ting Chen ◽  
Li-Mei Pai ◽  
Joanna Wesoly ◽  
Hans A.R. Bluyssen ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Type I Interferon ◽  
Plasmacytoid Dendritic Cell ◽  
Critical Role ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Type I Ifn ◽  
Flt3 Ligand ◽  
Lymphoid Progenitors

During infections and inflammation, plasmacytoid dendritic cells (pDCs) are the most potent type I interferon (IFN-I)–producing cells. However, the developmental origin of pDCs and the signals dictating pDC generation remain incompletely understood. Here, we report a synergistic role for IFN-I and Flt3 ligand (FL) in pDC development from common lymphoid progenitors (CLPs). Both conventional DCs (cDCs) and pDCs were generated from CLPs in response to FL, whereas pDC generation required higher concentrations of FL and concurrent IFN-I signaling. An absence of IFN-I receptor, impairment of IFN-I signaling, or neutralization of IFN-I significantly impeded pDC development from CLPs. Furthermore, FL induced IFN-I expression in CLPs, which in turn induced Flt3 up-regulation that facilitated survival and proliferation of CLPs, as well as their differentiation into pDCs. Collectively, these results define a critical role for the FL/IFN-I/Flt3 axis in pDC differentiation from CLPs.

scholarly journals Imperfect innate immune antagonism renders SARS-CoV-2 vulnerable towards IFN-γ and -λ

2020 ◽  
Author(s):  
Manuel Hayn ◽  
Maximilian Hirschenberger ◽  
Lennart Koepke ◽  
Jan H Straub ◽  
Rayhane Nchioua ◽  
...  
Keyword(s):  
Innate Immune System ◽  
Viral Infections ◽  
Innate Immune ◽  
Type I ◽  
Type Ii ◽  
Type I Ifn ◽  
Emerging Pathogens ◽  
Ifn Γ ◽  
The Impact ◽  
Different Levels

ABSTRACTThe innate immune system constitutes a powerful barrier against viral infections. However, it may fail because successful emerging pathogens, like SARS-CoV-2, evolved strategies to counteract it. Here, we systematically assessed the impact of 29 SARS-CoV-2 proteins on viral sensing, type I, II and III interferon (IFN) signaling, autophagy and inflammasome formation. Mechanistic analyses show that autophagy and type I IFN responses are effectively counteracted at different levels. For example, Nsp14 induces loss of the IFN receptor, whereas ORF3a disturbs autophagy at the Golgi/endosome interface. Comparative analyses revealed that antagonism of type I IFN and autophagy is largely conserved, except that SARS-CoV-1 Nsp15 is more potent in counteracting type I IFN than its SARS-CoV-2 ortholog. Altogether, however, SARS-CoV-2 counteracts type I IFN responses and autophagy much more efficiently than type II and III IFN signaling. Consequently, the virus is relatively resistant against exogenous IFN-α/β and autophagy modulation but remains highly vulnerable towards IFN-γ and -λ treatment. In combination, IFN-γ and -λ act synergistically, and drastically reduce SARS-CoV-2 replication at exceedingly low doses. Our results identify ineffective type I and II antagonism as weakness of SARS-CoV-2 that may allow to devise safe and effective anti-viral therapies based on targeted innate immune activation.

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