DDX41: a multifunctional DEAD-box protein involved in pre-mRNA splicing and innate immunity

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Alexandra Z. Andreou
Keyword(s):  
Innate Immunity ◽  
Nucleic Acid ◽  
Mrna Splicing ◽  
Innate Immune ◽  
Current Understanding ◽  
Rna Helicases ◽  
Immune Signaling ◽  
Dead Box ◽  
Innate Immune Signaling ◽  
Rna Export

Abstract DEAD-box helicases participate in nearly all steps of an RNA’s life. In recent years, increasing evidence has shown that several family members are multitasking enzymes. They are often involved in different processes, which may be typical for RNA helicases, such as RNA export and translation, or atypical, e.g., acting as nucleic acid sensors that activate downstream innate immune signaling. This review focuses on the DEAD-box protein DDX41 and summarizes our current understanding of its roles as an innate immunity sensor in the cytosol and in pre-mRNA splicing in the nucleus and discusses DDX41’s involvement in disease.

scholarly journals Pathogen-Associated Molecular Pattern Recognition of Hepatitis C Virus Transmitted/Founder Variants by RIG-I Is Dependent on U-Core Length

2015 ◽  
Vol 89 (21) ◽  
pp. 11056-11068 ◽  
Author(s):  
Alison Kell ◽  
Mark Stoddard ◽  
Hui Li ◽  
Joe Marcotrigiano ◽  
George M. Shaw ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Acute Infection ◽  
Innate Immune ◽  
Hcv Infection ◽  
Immune Signaling ◽  
Molecular Pattern ◽  
Innate Immune Signaling ◽  
Acute Hcv

ABSTRACTDespite the introduction of direct-acting antiviral (DAA) drugs against hepatitis C virus (HCV), infection remains a major public health concern because DAA therapeutics do not prevent reinfection and patients can still progress to chronic liver disease. Chronic HCV infection is supported by a variety of viral immune evasion strategies, but, remarkably, 20% to 30% of acute infections spontaneously clear prior to development of adaptive immune responses, thus implicating innate immunity in resolving acute HCV infection. However, the virus-host interactions regulating acute infection are unknown. Transmission of HCV involves one or a few transmitted/founder (T/F) variants. In infected hepatocytes, the retinoic acid-inducible gene I (RIG-I) protein recognizes 5′ triphosphate (5′ppp) of the HCV RNA and a pathogen-associated molecular pattern (PAMP) motif located within the 3′ untranslated region consisting of poly-U/UC. PAMP binding activates RIG-I to induce innate immune signaling and type 1 interferon antiviral defenses. HCV poly-U/UC sequences can differ in length and complexity, suggesting that PAMP diversity in T/F genomes could regulate innate immune control of acute HCV infection. Using 14 unique poly-U/UC sequences from HCV T/F genomes recovered from acute-infection patients, we tested whether RIG-I recognition and innate immune activation correlate with PAMP sequence characteristics. We show that T/F variants are recognized by RIG-I in a manner dependent on length of the U-core motif of the poly-U/UC PAMP and are recognized by RIG-I to induce innate immune responses that restrict acute infection. PAMP recognition of T/F HCV variants by RIG-I may therefore impart innate immune signaling and HCV restriction to impact acute-phase-to-chronic-phase transition.IMPORTANCERecognition of nonself molecular patterns such as those seen with viral nucleic acids is an essential step in triggering the immune response to virus infection. Innate immunity is induced by hepatitis C virus infection through the recognition of viral RNA by the cellular RIG-I protein, where RIG-I recognizes a poly-uridine/cytosine motif in the viral genome. Variation within this motif may provide an immune evasion strategy for transmitted/founder viruses during acute infection. Using 14 unique poly-U/UC sequences from HCV T/F genomes recovered from acutely infected HCV patients, we demonstrate that RIG-I binding and activation of innate immunity depend primarily on the length of the uridine core within this motif. T/F variants found in acute infection contained longer U cores within the motif and could activate RIG-I and induce innate immune signaling sufficient to restrict viral infection. Thus, recognition of T/F variants by RIG-I could significantly impact the transition from acute to chronic infection.

scholarly journals Spatiotemporal dynamics of innate immune signaling via RIG-I–like receptors

2020 ◽  
Vol 117 (27) ◽  
pp. 15778-15788 ◽  
Author(s):  
Katharina Esser-Nobis ◽  
Lauren D. Hatfield ◽  
Michael Gale
Keyword(s):  
Innate Immunity ◽  
Virus Infection ◽  
Rna Virus ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Negative Regulator ◽  
Resting Cells ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Irf3 Activation

RIG-I, MDA5, and LGP2 comprise the RIG-I–like receptors (RLRs). RIG-I and MDA5 are essential pathogen recognition receptors sensing viral infections while LGP2 has been described as both RLR cofactor and negative regulator. After sensing and binding to viral RNA, including double-stranded RNA (dsRNA), RIG-I and MDA5 undergo cytosol-to-membrane relocalization to bind and signal through the MAVS adaptor protein on intracellular membranes, thus directing downstream activation of IRF3 and innate immunity. Here, we report examination of the dynamic subcellular localization of all three RLRs within the intracellular response to dsRNA and RNA virus infection. Observations from high resolution biochemical fractionation and electron microscopy, coupled with analysis of protein interactions and IRF3 activation, show that, in resting cells, microsome but not mitochondrial fractions harbor the central components to initiate innate immune signaling. LGP2 interacts with MAVS in microsomes, blocking the RIG-I/MAVS interaction. Remarkably, in response to dsRNA treatment or RNA virus infection, LGP2 is rapidly released from MAVS and redistributed to mitochondria, temporally correlating with IRF3 activation. We reveal that IRF3 activation does not take place on mitochondria but instead occurs at endoplasmic reticulum (ER)-derived membranes. Our observations suggest ER-derived membranes as key RLR signaling platforms controlled through inhibitory actions of LGP2 binding to MAVS wherein LGP2 translocation to mitochondria releases MAVS inhibition to facilitate RLR-mediated signaling of innate immunity.

scholarly journals Sequential ubiquitination and deubiquitination enzymes synchronize the dual sensor and effector functions of TRIM21

2015 ◽  
Vol 112 (32) ◽  
pp. 10014-10019 ◽  
Author(s):  
Adam J. Fletcher ◽  
Donna L. Mallery ◽  
Ruth E. Watkinson ◽  
Claire F. Dickson ◽  
Leo C. James
Keyword(s):  
Innate Immunity ◽  
Essential Role ◽  
Innate Immune ◽  
Complex Mechanism ◽  
Immune Signaling ◽  
Effector Functions ◽  
Cytokine Induction ◽  
Innate Immune Signaling ◽  
Dual Sensor ◽  
Tripartite Motif

Tripartite motif (TRIM) 21 is a cytosolic antibody receptor that neutralizes antibody-coated viruses that penetrate the cell and simultaneously activates innate immunity. Here we show that the conjugation of TRIM21 with K63-linked ubiquitin (Ub-63Ub) catalyzed by the sequential activity of nonredundant E2 Ub enzymes is required for its dual antiviral functions. TRIM21 is first labeled with monoubiquitin (monoUb) by the E2 Ube2W. The monoUb is a substrate for the heterodimeric E2 Ube2N/Ube2V2, resulting in TRIM21-anchored Ub-63Ub. Depletion of either E2 abolishes Ub-63Ub and Ub-48Ub conjugation of TRIM21, NF-κB signaling, and virus neutralization. The formation of TRIM21-Ub-63Ub precedes proteasome recruitment, and we identify an essential role for the 19S-resident and degradation-coupled deubiquitinase Poh1 in TRIM21 neutralization, signaling, and cytokine induction. This study elucidates a complex mechanism of step-wise ubiquitination and deubiquitination activities that allows contemporaneous innate immune signaling and neutralization by TRIM21.

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