scholarly journals Lys29-linkage of ASK1 by Skp1−Cullin 1−Fbxo21 ubiquitin ligase complex is required for antiviral innate response

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Zhou Yu ◽  
Taoyong Chen ◽  
Xuelian Li ◽  
Mingjin Yang ◽  
Songqing Tang ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Type I Interferon ◽  
Innate Immune ◽  
Type I ◽  
Innate Response ◽  
Scf Complex ◽  
Protein Ubiquitination ◽  
Ubiquitin Ligase Complex ◽  
F Box Protein ◽  
Unknown Component

Protein ubiquitination regulated by ubiquitin ligases plays important roles in innate immunity. However, key regulators of ubiquitination during innate response and roles of new types of ubiquitination (apart from Lys48- and Lys63-linkage) in control of innate signaling have not been clearly understood. Here we report that F-box only protein Fbxo21, a functionally unknown component of SCF (Skp1–Cul1–F-box protein) complex, facilitates Lys29-linkage and activation of ASK1 (apoptosis signal-regulating kinase 1), and promotes type I interferon production upon viral infection. Fbxo21 deficiency in mice cells impairs virus-induced Lys29-linkage and activation of ASK1, attenuates c-Jun N-terminal kinase (JNK) and p38 signaling pathway, and decreases the production of proinflammatory cytokines and type I interferon, resulting in reduced antiviral innate response and enhanced virus replication. Therefore Fbxo21 is required for ASK1 activation via Lys29-linkage of ASK1 during antiviral innate response, providing mechanistic insights into non-proteolytic roles of SCF complex in innate immune response.

scholarly journals TRIM41 is required to innate antiviral response by polyubiquitinating BCL10 and recruiting NEMO

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Zhou Yu ◽  
Xuelian Li ◽  
Mingjin Yang ◽  
Jiaying Huang ◽  
Qian Fang ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
B Cell Lymphoma ◽  
Antiviral Response ◽  
Type I Interferons ◽  
Type I ◽  
Innate Response ◽  
Innate Antiviral Response

AbstractSensing of pathogenic nucleic acids by pattern recognition receptors (PRR) not only initiates anti-microbe defense but causes inflammatory and autoimmune diseases. E3 ubiquitin ligase(s) critical in innate response need to be further identified. Here we report that the tripartite motif-containing E3 ubiquitin ligase TRIM41 is required to innate antiviral response through facilitating pathogenic nucleic acids-triggered signaling pathway. TRIM41 deficiency impairs the production of inflammatory cytokines and type I interferons in macrophages after transfection with nucleic acid-mimics and infection with both DNA and RNA viruses. In vivo, TRIM41 deficiency leads to impaired innate response against viruses. Mechanistically, TRIM41 directly interacts with BCL10 (B cell lymphoma 10), a core component of CARD proteins−BCL10 − MALT1 (CBM) complex, and modifies the Lys63-linked polyubiquitylation of BCL10, which, in turn, hubs NEMO for activation of NF-κB and TANK-binding kinase 1 (TBK1) − interferon regulatory factor 3 (IRF3) pathways. Our study suggests that TRIM41 is the potential universal E3 ubiquitin ligase responsible for Lys63 linkage of BCL10 during innate antiviral response, adding new insight into the molecular mechanism for the control of innate antiviral response.

scholarly journals Type I interferon potentiates metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice

2020 ◽  
Author(s):  
Yuanjiu Lei ◽  
Camila Guerra Martinez ◽  
Sylvia Torres-Odio ◽  
Samantha L. Bell ◽  
Christine E. Birdwell ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Inflammatory Responses ◽  
Type I Interferon ◽  
Aerobic Glycolysis ◽  
Accelerated Aging ◽  
Innate Immune ◽  
Related Factor ◽  
Type I ◽  
Metabolic Dysfunction ◽  
Polymerase Gamma

AbstractMitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune crosstalk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA (mtDNA) instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces healthspan, and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling suppresses activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which increases oxidative stress, enhances pro-inflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyper-inflammatory phenotypes by restoring Nrf2 activity and reducing aerobic glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in aged mutator mice. These findings further advance our knowledge of how mitochondrial dysfunction shapes innate immune responses and provide a framework for understanding mitochondria-driven immunopathology in POLG-related diseases and aging.

scholarly journals Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

2015 ◽  
Vol 90 (5) ◽  
pp. 2403-2417 ◽  
Author(s):  
Chuan Xia ◽  
Madhuvanthi Vijayan ◽  
Curtis J. Pritzl ◽  
Serge Y. Fuchs ◽  
Adrian B. McDermott ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Influenza A Virus ◽  
Influenza A ◽  
Type I Interferon ◽  
Innate Immune ◽  
Host Cells ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns ◽  
Ha Protein

ABSTRACTInfluenza A virus (IAV) employs diverse strategies to circumvent type I interferon (IFN) responses, particularly by inhibiting the synthesis of type I IFNs. However, it is poorly understood if and how IAV regulates the type I IFN receptor (IFNAR)-mediated signaling mode. In this study, we demonstrate that IAV induces the degradation of IFNAR subunit 1 (IFNAR1) to attenuate the type I IFN-induced antiviral signaling pathway. Following infection, the level of IFNAR1 protein, but not mRNA, decreased. Indeed, IFNAR1 was phosphorylated and ubiquitinated by IAV infection, which resulted in IFNAR1 elimination. The transiently overexpressed IFNAR1 displayed antiviral activity by inhibiting virus replication. Importantly, the hemagglutinin (HA) protein of IAV was proved to trigger the ubiquitination of IFNAR1, diminishing the levels of IFNAR1. Further, influenza A viral HA1 subunit, but not HA2 subunit, downregulated IFNAR1. However, viral HA-mediated degradation of IFNAR1 was not caused by the endoplasmic reticulum (ER) stress response. IAV HA robustly reduced cellular sensitivity to type I IFNs, suppressing the activation of STAT1/STAT2 and induction of IFN-stimulated antiviral proteins. Taken together, our findings suggest that IAV HA causes IFNAR1 degradation, which in turn helps the virus escape the powerful innate immune system. Thus, the research elucidated an influenza viral mechanism for eluding the IFNAR signaling pathway, which could provide new insights into the interplay between influenza virus and host innate immunity.IMPORTANCEInfluenza A virus (IAV) infection causes significant morbidity and mortality worldwide and remains a major health concern. When triggered by influenza viral infection, host cells produce type I interferon (IFN) to block viral replication. Although IAV was shown to have diverse strategies to evade this powerful, IFN-mediated antiviral response, it is not well-defined if IAV manipulates the IFN receptor-mediated signaling pathway. Here, we uncovered that influenza viral hemagglutinin (HA) protein causes the degradation of type I IFN receptor subunit 1 (IFNAR1). HA promoted phosphorylation and polyubiquitination of IFNAR1, which facilitated the degradation of this receptor. The HA-mediated elimination of IFNAR1 notably decreased the cells' sensitivities to type I IFNs, as demonstrated by the diminished expression of IFN-induced antiviral genes. This discovery could help us understand how IAV regulates the host innate immune response to create an environment optimized for viral survival in host cells.

scholarly journals FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity

2020 ◽  
Vol 6 (38) ◽  
pp. eabc8561 ◽  
Author(s):  
Jun Ren ◽  
Mingming Sun ◽  
Hao Zhou ◽  
Amir Ajoolabady ◽  
Yuan Zhou ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Ubiquitin Ligase ◽  
High Fat Diet ◽  
Dependent Manner ◽  
Cardiac Damage ◽  
Ubiquitin Ligase Complex ◽  
F Box Protein ◽  
Trisphosphate Receptor ◽  
Type 3 ◽  
Mitochondrial Anomalies

Defective mitophagy is causally linked to obesity complications. Here, we identified an interaction between mitophagy protein FUNDC1 (FUN14 domain containing 1) and receptor subunit of human SCF (SKP1/cullin/F-box protein) ubiquitin ligase complex FBXL2 as a gatekeeper for mitochondrial Ca2+ homeostasis through degradation of IP3R3 (inositol 1,4,5-trisphosphate receptor type 3). Loss of FUNDC1 in FUNDC1−/− mice accentuated high-fat diet–induced cardiac remodeling, functional and mitochondrial anomalies, cell death, rise in IP3R3, and Ca2+ overload. Mass spectrometry and co-immunoprecipitation analyses revealed an interaction between FUNDC1 and FBXL2. Truncated mutants of Fbox (Delta-F-box) disengaged FBXL2 interaction with FUNDC1. Activation or transfection of FBXL2, inhibition of IP3R3 alleviated, whereas disruption of FBXL2 localization sensitized lipotoxicity-induced cardiac damage. FUNDC1 deficiency accelerated and decelerated palmitic acid–induced degradation of FBXL2 and IP3R3, respectively. Our data suggest an essential role for interaction between FUNDC1 and FBXL2 in preserving mitochondrial Ca2+ homeostasis and cardiac function in obese hearts.

scholarly journals Vitamin D Potentiates the Inhibitory Effect of MicroRNA-130a in Hepatitis C Virus Replication Independent of Type I Interferon Signaling Pathway

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Xiaoqiong Duan ◽  
Yujuan Guan ◽  
Yujia Li ◽  
Shan Chen ◽  
Shilin Li ◽  
...  
Keyword(s):  
Vitamin D ◽  
Type I Interferon ◽  
Inhibitory Effect ◽  
Therapeutic Strategies ◽  
Innate Immune ◽  
Type I ◽  
Interferon Signaling ◽  
Host Innate Immune Response ◽  
Antiviral Mechanism

Calcitriol, the bioactive metabolite of vitamin D, was reported to inhibit HCV production in a synergistic fashion with interferon, a treatmentin vitro. Our previous study established that miR-130a inhibits HCV replication by restoring the host innate immune response. We aimed to determine whether there is additive inhibitory effect of calcitriol and miR-130a on HCV replication. Here we showed that calcitriol potentiates the anti-HCV effect of miR-130a in both Con1b replicon and J6/JFH1 culture systems. Intriguingly, this potentiating effect of calcitriol on miR-130a was not through upregulating the expression of cellular miR-130a or through increasing the miR-130a-mediated IFNα/βproduction. All these findings may contribute to the development of novel anti-HCV therapeutic strategies although the antiviral mechanism needs to be further investigated.

scholarly journals NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4

2012 ◽  
Vol 13 (4) ◽  
pp. 387-395 ◽  
Author(s):  
Jun Cui ◽  
Yinyin Li ◽  
Liang Zhu ◽  
Dan Liu ◽  
Zhou Songyang ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Signaling

scholarly journals Phyllopod Acts as an Adaptor Protein To Link the Sina Ubiquitin Ligase to the Substrate Protein Tramtrack

2002 ◽  
Vol 22 (19) ◽  
pp. 6854-6865 ◽  
Author(s):  
Songhui Li ◽  
Chunyan Xu ◽  
Richard W. Carthew
Keyword(s):  
Ubiquitin Ligase ◽  
Neuronal Development ◽  
Adaptor Protein ◽  
Ras Signaling ◽  
Binding Domains ◽  
Substrate Protein ◽  
Ras Activation ◽  
Ubiquitin Ligase Complex ◽  
Acid Domain ◽  
F Box Protein

ABSTRACT The RING domain protein Sina, together with Phyllopod and the F-box protein Ebi, forms a Ras-regulated E3 ubiquitin ligase complex that activates photoreceptor cell differentiation in the eye of Drosophila melanogaster. The expression of Phyllopod is induced upon Ras activation, allowing the complex to degrade the transcription repressor Tramtrack and removing its block of neuronal development in photoreceptor precursors. We show that Phyllopod functions as an adaptor in the complex, physically linking Sina with Tramtrack via separate binding domains. One 19-amino-acid domain in Phyllopod interacts with a region of Sina's SBD domain. Another domain in Phyllopod interacts with a C-terminal helix in the POZ domain of Tramtrack. This interaction is specific to the Tramtrack POZ domain and not to other POZ domain proteins present in photoreceptor precursors. Degradation of Tramtrack is dependent upon association of Sina with its cognate binding site in Phyllopod. These results illustrate how Ras signaling can modulate an E3 ligase activity not by the phosphorylation of substrate proteins but by regulating the expression of specific E3 adaptors.

scholarly journals The Abundance of Met30p Limits SCFMet30p Complex Activity and Is Regulated by Methionine Availability

2000 ◽  
Vol 20 (21) ◽  
pp. 7845-7852 ◽  
Author(s):  
Dechelle B. Smothers ◽  
Lukasz Kozubowski ◽  
Cheryl Dixon ◽  
Mark G. Goebl ◽  
Neal Mathias
Keyword(s):  
Ubiquitin Ligase ◽  
Environmental Conditions ◽  
Cellular Responses ◽  
Biological Pathways ◽  
Variable Component ◽  
Complex Activity ◽  
Scf Complex ◽  
Ubiquitin Ligase Activity ◽  
F Box Protein

ABSTRACT Ubiquitin-mediated degradation plays a crucial role in many fundamental biological pathways, including the mediation of cellular responses to changes in environmental conditions. A family of ubiquitin ligase complexes, called SCF complexes, found throughout eukaryotes, is involved in a variety of biological pathways. In Saccharomyces cerevisiae, an SCF complex contains a common set of components, namely, Cdc53p, Skp1p, and Hrt1p. Substrate specificity is defined by a variable component called an F-box protein. The F- box is a ∼40-amino-acid motif that allows the F-box protein to bind Skp1p. Each SCF complex recognizes different substrates according to which F-box protein is associated with the complex. In yeasts, three SCF complexes have been demonstrated to associate with the ubiquitin-conjugating enzyme Cdc34p and have ubiquitin ligase activity. F-box proteins are not abundant and are unstable. As part of the SCFMet30p complex, the F-box protein Met30p represses methionine biosynthetic gene expression when availability ofl-methionine is high. Here we demonstrate that in vivo SCFMet30p complex activity can be regulated by the abundance of Met30p. Furthermore, we provide evidence that Met30p abundance is regulated by the availability of l-methionine. We propose that the cellular responses mediated by an SCF complex are directly regulated by environmental conditions through the control of F-box protein stability.

scholarly journals The Severe Acute Respiratory Syndrome Coronavirus Nucleocapsid Inhibits Type I Interferon Production by Interfering with TRIM25-Mediated RIG-I Ubiquitination

2017 ◽  
Vol 91 (8) ◽  
Author(s):  
Yong Hu ◽  
Wei Li ◽  
Ting Gao ◽  
Yan Cui ◽  
Yanwen Jin ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Type I Interferon ◽  
Sendai Virus ◽  
Innate Immune ◽  
Atypical Pneumonia ◽  
Type I ◽  
Spry Domain ◽  
N Protein ◽  
Host Interaction ◽  
C Terminus

ABSTRACT Severe acute respiratory syndrome (SARS) is a respiratory disease, caused by a coronavirus (SARS-CoV), that is characterized by atypical pneumonia. The nucleocapsid protein (N protein) of SARS-CoV plays an important role in inhibition of type I interferon (IFN) production via an unknown mechanism. In this study, the SARS-CoV N protein was found to bind to the SPRY domain of the tripartite motif protein 25 (TRIM25) E3 ubiquitin ligase, thereby interfering with the association between TRIM25 and retinoic acid-inducible gene I (RIG-I) and inhibiting TRIM25-mediated RIG-I ubiquitination and activation. Type I IFN production induced by poly I·C or Sendai virus (SeV) was suppressed by the SARS-CoV N protein. SARS-CoV replication was increased by overexpression of the full-length N protein but not N amino acids 1 to 361, which could not interact with TRIM25. These findings provide an insightful interpretation of the SARS-CoV-mediated host innate immune suppression caused by the N protein. IMPORTANCE The SARS-CoV N protein is essential for the viral life cycle and plays a key role in the virus-host interaction. We demonstrated that the interaction between the C terminus of the N protein and the SPRY domain of TRIM25 inhibited TRIM25-mediated RIG-I ubiquitination, which resulted in the inhibition of IFN production. We also found that the Middle East respiratory syndrome CoV (MERS-CoV) N protein interacted with TRIM25 and inhibited RIG-I signaling. The outcomes of these findings indicate the function of the coronavirus N protein in modulating the host's initial innate immune response.

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