scholarly journals A mutation in POLR3E impairs antiviral immune response and RNA polymerase III

2020 ◽  
Vol 117 (36) ◽  
pp. 22113-22121
Author(s):  
Aravind Ramanathan ◽  
Michael Weintraub ◽  
Natalie Orlovetskie ◽  
Raphael Serruya ◽  
Dhivakar Mani ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Virus ◽  
Rna Polymerase Iii ◽  
Innate Immune ◽  
Type I Interferons ◽  
Homozygous Mutation ◽  
Type I ◽  
Protein Subunit ◽  
Antiviral Immune Response ◽  
Pol Iii

RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.

scholarly journals MAVS Self-Association Mediates Antiviral Innate Immune Signaling

2009 ◽  
Vol 83 (8) ◽  
pp. 3420-3428 ◽  
Author(s):  
Eric D. Tang ◽  
Cun-Yu Wang
Keyword(s):  
Rna Virus ◽  
Innate Immune ◽  
Type I Interferons ◽  
Mitochondrial Outer Membrane ◽  
Type I ◽  
Rna Helicases ◽  
Downstream Effector ◽  
Innate Immune Signaling ◽  
Self Association ◽  
Tm Domain

ABSTRACT The innate immune system recognizes nucleic acids during viral infection and stimulates cellular antiviral responses. Intracellular detection of RNA virus infection is mediated by the RNA helicases RIG-I (retinoic acid inducible gene I) and MDA-5, which recognize viral RNA and signal through the adaptor molecule MAVS (mitochondrial antiviral signaling) to stimulate the phosphorylation and activation of the transcription factors IRF3 (interferon regulatory factor 3) and IRF7. Once activated, IRF3 and IRF7 turn on the expression of type I interferons, such as beta interferon. Interestingly, unlike other signaling molecules identified in this pathway, MAVS contains a C-terminal transmembrane (TM) domain that is essential for both type I interferon induction and localization of MAVS to the mitochondrial outer membrane. However, the role the MAVS TM domain plays in signaling remains unclear. Here we report the identification of a function for the TM domain in mediating MAVS self-association. The activation of RIG-I/MDA-5 leads to the TM-dependent dimerization of the MAVS N-terminal caspase recruitment domain, thereby providing an interface for direct binding to and activation of the downstream effector TRAF3 (tumor necrosis factor receptor-associated factor 3). Our results reveal a role for MAVS self-association in antiviral innate immunity signaling and provide a molecular mechanism for downstream signal transduction.

scholarly journals RNA Polymerase III Detects Cytosolic DNA and Induces Type I Interferons through the RIG-I Pathway

Cell ◽  
2009 ◽  
Vol 138 (3) ◽  
pp. 576-591 ◽  
Author(s):  
Yu-Hsin Chiu ◽  
John B. MacMillan ◽  
Zhijian J. Chen
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Iii ◽  
Type I Interferons ◽  
Type I ◽  
Polymerase Iii

scholarly journals Fas-Associated Factor 1 Negatively Regulates the Antiviral Immune Response by Inhibiting Translocation of Interferon Regulatory Factor 3 to the Nucleus

2016 ◽  
Vol 36 (7) ◽  
pp. 1136-1151 ◽  
Author(s):  
Soonhwa Song ◽  
Jae-Jin Lee ◽  
Hee-Jung Kim ◽  
Jeong Yoon Lee ◽  
Jun Chang ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Antiviral Response ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Antiviral Immune Response ◽  
Associated Factor

This study is designed to examine the cellular functions of human Fas-associated factor 1 (FAF1) containing multiple ubiquitin-related domains. Microarray analyses revealed that interferon-stimulated genes related to the antiviral response are significantly increased in FAF1-knockdown HeLa cells. Silencing FAF1 enhanced the poly(I·C)- and respiratory syncytial virus (RSV)-induced production of type I interferons (IFNs), the target genes of interferon regulator factor 3 (IRF3). IRF3 is a key transcription factor in IFN-β signaling responsible for the host innate immune response. This study also found that FAF1 and IRF3 physically associate with IPO5/importin-β3 and that overexpression of FAF1 reduces the interaction between IRF3 and IPO5/importin-β3. These findings suggest that FAF1 negatively regulates IRF3-mediated IFN-β production and the antiviral innate immune response by regulating nuclear translocation of IRF3. We conclude that FAF1 plays a novel role in negatively regulating virus-induced IFN-β production and the antiviral response by inhibiting the translocation of active, phosphorylated IRF3 from the cytosol to the nucleus.

scholarly journals ZCCHC3 modulates TLR3-mediated signaling by promoting recruitment of TRIF to TLR3

2020 ◽  
Vol 12 (4) ◽  
pp. 251-262
Author(s):  
Ru Zang ◽  
Huan Lian ◽  
Xuan Zhong ◽  
Qing Yang ◽  
Hong-Bing Shu
Keyword(s):  
Rna Virus ◽  
Interleukin 1 ◽  
Innate Immune ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Antiviral Genes ◽  
Ligand Stimulation ◽  
Tlr3 Ligand Poly ◽  
Receptor Domain

Abstract Toll-like receptor 3 (TLR3)-mediated signaling is important for host defense against RNA virus. Upon viral RNA stimulation, toll and interleukin-1 receptor domain-containing adaptor inducing IFN-β (TRIF) is recruited to TLR3 and then undergoes oligomerization, which is required for the recruitment of downstream molecules to transmit signals. Here, we identified zinc finger CCHC-type containing 3 (ZCCHC3) as a positive regulator of TLR3-mediated signaling. Overexpression of ZCCHC3 promoted transcription of downstream antiviral genes stimulated by the synthetic TLR3 ligand poly(I:C). ZCCHC3-deficiency markedly inhibited TLR3- but not TLR4-mediated induction of type I interferons (IFNs) and proinflammatory cytokines. Zcchc3−/− mice were more resistant to poly(I:C)- but not lipopolysaccharide-induced inflammatory death. Mechanistically, ZCCHC3 promoted recruitment of TRIF to TLR3 after poly(I:C) stimulation. Our findings reveal that ZCCHC3 plays an important role in TLR3-mediated innate immune response by promoting the recruitment of TRIF to TLR3 after ligand stimulation.

scholarly journals NDR2 promotes the antiviral immune response via facilitating TRIM25-mediated RIG-I activation in macrophages

2019 ◽  
Vol 5 (2) ◽  
pp. eaav0163 ◽  
Author(s):  
Zhiyong Liu ◽  
Cheng Wu ◽  
Yueyun Pan ◽  
Huan Liu ◽  
Xiumei Wang ◽  
...  
Keyword(s):  
Immune Response ◽  
Rna Virus ◽  
Conditional Knockout ◽  
Type I Interferons ◽  
Type I ◽  
Posttranslational Regulation ◽  
Antiviral Immune Response ◽  
Syncytial Virus ◽  
Antiviral Innate Immunity ◽  
Inducible Gene

Retinoic acid–inducible gene I (RIG-I), a pivotal cytosolic sensor, recognizes viral RNAs to initiate antiviral innate immunity. However, posttranslational regulation of RIG-I signaling is not well understood. We report here that nuclear Dbf2-related kinase 2 (NDR2) functions as a crucial positive regulator of the RIG-I–mediated antiviral immune response. Overexpression of NDR2 or its kinase-inactive mutants potentiates RNA virus–induced production of type I interferons and proinflammatory cytokines and dampens viral replication. NDR2 conditional knockout mice (Lysm+NDR2f/f) show an impaired antiviral immune response. Mechanistically, NDR2 directly associates with RIG-I and TRIM25, thus facilitating the RIG-I/TRIM25 complex and enhancing the TRIM25-mediated K63-linked polyubiquitination of RIG-I, which is required for the RIG-I–mediated antiviral immune response. Furthermore, NDR2 expression is notably down-regulated in peripheral blood from respiratory syncytial virus–infected patients and in virus-infected macrophages. Collectively, these findings provide insights into the function of NDR2 in antiviral immunity and its related clinical significance.

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