c-Cbl-mediated ubiquitination of IRF3 negatively regulates IFN-β production and cellular antiviral response

Zhao, Xibao; Zhu, Huihui; Yu, Juan; Li, Hongrui; Ge, Jiafeng; Chen, Weilin

doi:10.1016/j.cellsig.2016.08.002

Cited by 45 publications

(25 citation statements)

References 41 publications

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“…Thus, while loss of CBL results in increased sensitivity to Mtb infection, it also creates a more restrictive environment for viral replication. This is consistent with recent findings that siRNA-mediated depletion of CBL results in stabilization of IRF3 and increased anti-viral signaling (Zhao et al, 2016), though when we evaluated whether CBL similarly regulated IRF3 during Mtb infection we detected no change in protein levels ( Figure 5I).…”

Section: Cbl Regulates the Balance Between Cell-intrinsic Anti-bactersupporting

confidence: 92%

An Mtb-Human Protein-Protein Interaction Map Reveals that Bacterial LpqN Antagonizes CBL, a Host Ubiquitin Ligase that Regulates the Balance Between Anti-Viral and Anti-Bacterial Responses

Penn

Netter

Johnson

et al. 2017

Preprint

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Although macrophages are armed with potent anti-bacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophageintrinsic bacterial control, and the Mtb strategies to overcome them are poorly understood. To further study these processes, we used a systematic affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein interactions (PPIs) involving 34 secreted Mtb proteins. This interaction map revealed two new factors involved in Mtb pathogenesis -the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL. We discovered that an lpqN Mtb mutant is attenuated in macrophages, but growth is restored when CBL is removed. Conversely, Cbl -/macrophages are resistant to viral infection, indicating that CBL regulates cell-intrinsic polarization between anti-bacterial and anti-viral immunity. Collectively, these findings illustrate the utility of this Mtb-human PPI map as a resource for developing a deeper understanding of the intricate interactions between Mtb and its host.

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Section: Cbl Regulates the Balance Between Cell-intrinsic Anti-bactersupporting

confidence: 92%

An Mtb-Human Protein-Protein Interaction Map Reveals that Bacterial LpqN Antagonizes CBL, a Host Ubiquitin Ligase that Regulates the Balance Between Anti-Viral and Anti-Bacterial Responses

Penn

Netter

Johnson

et al. 2017

Preprint

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“…Besides conjugated Ub, unanchored Ub chains (Lys63-or Lys48-linked) also seem to play a role in the regulation of innate immune signaling by providing a multimeric scaffold for the activation of RIG-I and MDA-5 complexes [43][44][45]. In addition, ubiquitination of IRF3 has been observed and implicated in the induction of cellular proapoptotic pathways [46] and in the negative regulation of IFN-β signaling [47].…”

Section: Antiviral Innate Immune Response and Its Regulation By Ubmentioning

confidence: 99%

Structure and Function of Viral Deubiquitinating Enzymes

Bailey-Elkin

Knaap

Kikkert

et al. 2017

Journal of Molecular Biology

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Post-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes, including innate and adaptive immune responses. Ubiquitin-mediated control over these processes can be reversed by cellular deubiquitinating enzymes (DUBs), which remove ubiquitin from cellular targets and depolymerize polyubiquitin chains. The importance of protein ubiquitination to host immunity has been underscored by the discovery of viruses that encode proteases with deubiquitinating activity, many of which have been demonstrated to actively corrupt cellular ubiquitin-dependent processes to suppress innate antiviral responses and promote viral replication. DUBs have now been identified in diverse viral lineages, and their characterization is providing valuable insights into virus biology and the role of the ubiquitin system in host antiviral mechanisms. Here, we provide an overview of the structural biology of these fascinating viral enzymes and their role innate immune evasion and viral replication.

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“…Additionally, Polo-like kinase (PLK) 2 is associated with IRF3 nuclear translocation (8). In contrast, multiple proteins, including PIN1, YAP, RBCK1, RAUL, PTEN, PP2A, MAPK phosphatase 5, SENP2, TRIM21 (Ro52), TRIM26, FoxO1, c-cbl, Rubicon, ERRa, MST1, and AGO2, have been reported to negatively regulate IRF3 activation via distinct mechanisms such as proteasome-dependent degradation, dephosphorylation, de-SUMOylation, and/or prevention of protein-protein interactions (9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

Hu Antigen R Regulates Antiviral Innate Immune Responses through the Stabilization of mRNA for Polo-like Kinase 2

Sueyoshi

Kawasaki

Kitai

et al. 2018

The Journal of Immunology

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Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), RIG-I, and melanoma differentiation-associated gene 5 (MDA5) play a critical role in inducing antiviral innate immune responses by activating IFN regulatory factor 3 (IRF3) and NF-κB, which regulates the transcription of type I IFN and inflammatory cytokines. Antiviral innate immune responses are also regulated by posttranscriptional and translational mechanisms. In this study, we identified an RNA-binding protein HuR as a regulator for RLR signaling. Overexpression of HuR, but not of other Hu members, increased IFN-β promoter activity. HuR-deficient macrophage cells exhibited decreased expression after RLR stimulation, whereas they showed normal induction after stimulation with bacterial LPS or immunostimulatory DNA. Moreover, HuR-deficient cells displayed impaired nuclear translocation of IRF3 after RLR stimulation. In HuR-deficient cells, the mRNA expression of Polo-like kinase (PLK) 2 was markedly reduced. We found that HuR bound to the 3' untranslated region of mRNA and increased its stabilization. PLK2-deficient cells also showed reduced IRF3 nuclear translocation and mRNA expression during RLR signaling. Together, these findings suggest that HuR bolsters RLR-mediated IRF3 nuclear translocation by controlling the stability of mRNA.

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c-Cbl-mediated ubiquitination of IRF3 negatively regulates IFN-β production and cellular antiviral response

Cited by 45 publications

References 41 publications

An Mtb-Human Protein-Protein Interaction Map Reveals that Bacterial LpqN Antagonizes CBL, a Host Ubiquitin Ligase that Regulates the Balance Between Anti-Viral and Anti-Bacterial Responses

An Mtb-Human Protein-Protein Interaction Map Reveals that Bacterial LpqN Antagonizes CBL, a Host Ubiquitin Ligase that Regulates the Balance Between Anti-Viral and Anti-Bacterial Responses

Structure and Function of Viral Deubiquitinating Enzymes

Hu Antigen R Regulates Antiviral Innate Immune Responses through the Stabilization of mRNA for Polo-like Kinase 2

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