Rac1 and PAK1 are upstream of IKK‐ε and TBK‐1 in the viral activation of interferon regulatory factor‐3

Ehrhardt, Christina; Kardinal, Christian; Wurzer, Walter J.; Wolff, Thorsten; Eichel‐Streiber, Christoph von; Pleschka, Stephan; Planz, Oliver; Ludwig, Stephan

doi:10.1016/j.febslet.2004.04.069

Cited by 117 publications

(106 citation statements)

References 36 publications

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“…These studies have led to the characterization of new inducers of IRF-3 activity as well as the intracellular signaling pathways leading to IRF-3 activation (38,42,43,55,56). Notably, two IKK homologs, IKKi and TBK1, were shown to be involved in IRF-3 phosphorylation and activation (12)(13)(14)(15)(16)57). Another important issue, which remains poorly understood, is the molecular mechanisms that trigger the degradation of IRF-3 following virus infection.…”

Section: Discussionmentioning

confidence: 99%

Involvement of the IκB Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation

Bibeau-Poirier¹,

Gravel²,

Clément³

et al. 2006

The Journal of Immunology

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Activation of the innate arm of the immune system following pathogen infection relies on the recruitment of latent transcription factors involved in the induction of a subset of genes responsible for viral clearance. One of these transcription factors, IFN regulatory factor 3 (IRF-3), is targeted for proteosomal degradation following virus infection. However, the molecular mechanisms involved in this process are still unknown. In this study, we show that polyubiquitination of IRF-3 increases in response to Sendai virus infection. Using an E1 temperature-sensitive cell line, we demonstrate that polyubiquitination is required for the observed degradation of IRF-3. Inactivation of NEDD8-activating E1 enzyme also results in stabilization of IRF-3 suggesting the NEDDylation also plays a role in IRF-3 degradation following Sendai virus infection. In agreement with this observation, IRF-3 is recruited to Cullin1 following virus infection and overexpression of a dominant-negative mutant of Cullin1 significantly inhibits the degradation of IRF-3 observed in infected cells. We also asked whether the C-terminal cluster of phosphoacceptor sites of IRF-3 could serve as a destabilization signal and we therefore measured the half-life of C-terminal phosphomimetic IRF-3 mutants. Interestingly, we found them to be short-lived in contrast to wild-type IRF-3. In addition, no degradation of IRF-3 was observed in TBK1−/− mouse embryonic fibroblasts. All together, these data demonstrate that virus infection stimulates a host cell signaling pathway that modulates the expression level of IRF-3 through its C-terminal phosphorylation by the IκB kinase-related kinases followed by its polyubiquitination, which is mediated in part by a Cullin-based ubiquitin ligase.

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Section: Discussionmentioning

confidence: 99%

Involvement of the IκB Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation

Bibeau-Poirier¹,

Gravel²,

Clément³

et al. 2006

The Journal of Immunology

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“…We therefore went on to address whether this unique phosphorylation plays a physiological role in the regulation of IRF3 function. Although JNK could also stimulate the transcriptional activity of another transcription factor, alkaline phosphatase (AP-1), the PRD III-I-Luciferase reporter was responsive only to IRF3 activation in the context of LPS stimulation [39]. As shown in Figure 4A, luciferase analysis revealed that inhibition of endogenous JNK activation by SP600125 significantly impaired gene expression induced by LPS, which reduced the expression level below the basal level.…”

Section: Jnk Regulates Irf3-mediated Gene Expression Induced By Lps Amentioning

confidence: 98%

The TAK1-JNK cascade is required for IRF3 function in the innate immune response

Zhang

Chen

et al. 2009

Cell Res

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Interferon regulatory factor (IRF)3 is critical for the transcriptional induction of chemokines and cytokines during viral or bacterial invasion. The kinases Tank binding kinase (TBK)1 and Ikappa B kinase (IKK)ε can phosphorylate the C-terminal part of IRF3 and play important roles in IRF3 activation. In this study, we show that another kinase, c-Jun-NH 2 -terminal kinase (JNK), phosphorylates IRF3 on its N-terminal serine 173 residue, and TAK1 can stimulate IRF3 phosphorylation via JNK. JNK specific inhibitor SP600125 inhibits the N-terminal phosphorylation without affecting the C-terminal phosphorylation. In addition, IRF3-mediated gene expressions on lipopolysaccharide (LPS) or polyinosinic-cytidylic acid (polyI:C) treatment are severely impaired by SP600125, as well as for reporter gene assay of IRF3 activation. Knockdown of TAK1 further confirmed these observations. Interestingly, constitutive active IRF3(5D) can be inhibited by SP600125; JNK1 can synergize the action of IRF3(5D), but not the S173A-IRF3(5D) mutant. More importantly, polyI:C failed to induce the phosphorylation of mutant S173A and SP600125 dramatically abrogated IRF3 phosphorylation and dimerization that was stimulated by polyI:C. Thus, this study demonstrates that the TAK1-JNK cascade is required for IRF3 function, in addition to TBK1/IKKε, uncovering a new mechanism for mitogen-activated protein (MAP) kinase to regulate the innate immunity.

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Section: Methodsmentioning

confidence: 99%

“…pcDNA3-TBK1 and pcDNA3-IKKe expression plasmids were kind gifts from Dr K. Fitzgerald (Fitzgerald et al, 2003). The reporter plasmid (PRDIII-I) 4 -Luc was kindly provided by Dr S. Ludwig (Ehrhardt et al, 2004).Transfection and reporter assay. 293T cells were seeded in 35 mm dishes and co-transfected with empty vector or plasmids encoding the PRRSV proteins, Renilla luciferase plasmid phRL-TK and reporter plasmid p125-Luc, PRD(III-I)4-Luc or pNF-kB-Luc.…”

mentioning

confidence: 99%

The cysteine protease domain of porcine reproductive and respiratory syndrome virus non-structural protein 2 antagonizes interferon regulatory factor 3 activation

Zheng

Zhou

et al. 2010

Journal of General Virology

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There is growing evidence that porcine reproductive and respiratory syndrome virus (PRRSV) has developed mechanisms to subvert the host innate immune response. PRRSV non-structural protein 2 (Nsp2) was suggested previously as a potential interferon (IFN) antagonist. This study focused on Nsp2 to investigate its inhibitory mechanism of IFN induction. It was demonstrated that Nsp2 strongly inhibited IFN-b production by antagonizing activation of the IFN regulatory factor 3 (IRF-3) pathway induced by the Sendai virus (SeV). Further studies revealed that the cysteine protease domain (PL2) of Nsp2 was necessary for IFN antagonism. Additionally, both full-length Nsp2 and the PL2 protease domain of Nsp2 were found to inhibit SeV-induced phosphorylation and nuclear translocation of IRF-3. These findings suggest that Nsp2 is likely to play an important role in subversion of IRF-3-dependent innate antiviral defences, providing a basis for elucidating the mechanisms underlying PRRSV pathogenesis. INTRODUCTIONThe production of type I interferons (IFN-a/b) plays a pivotal role in the host antiviral immune defence (Bonjardim, 2005). Cellular sensors capable of recognizing various viral determinants initiate IFN signal transduction. Positive-stranded RNA viruses can generate intermediate dsRNA during replication, which is an efficient inducer of type I IFNs. This intermediate dsRNA can trigger a cascade of cellular sensors, resulting in type I IFN production and secretion (Kawai & Akira, 2006a;Randall & Goodbourn, 2008). The induction of type I IFNs is initiated via recognition of a pathogen-associated molecule in dsRNA by cellular pattern recognition receptors, including Tolllike receptor 3 (TLR3), caspase recruitment domain (CARD)-containing proteins, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 . TLR3 signals through the adaptor molecule Toll-interleukin-1-resistance domain-containing adaptor inducing IFN-b (TRIF), whilst MDA-5 and RIG-I signal through the adaptor molecule mitochondrial antiviral signal protein (MAVS; also known as IPS-1, Cardif and VISA) to activate a type I IFN response (Kawai & Akira, 2006b; Kawai et al., 2005; Yamamoto et al., 2003). Despite utilizing different adaptors, both pathways converge to activate two downstream kinases, TANK-binding kinase 1 (TBK-1) and inhibitor of kB kinase e (IKKe), subsequently leading to the activation of latent IFN transcription factors, including IFN regulatory factors (IRF-3 and/or IRF-7), nuclear factor-kB (NF-kB) and activating protein 1 (AP-1) (Fitzgerald et al., 2003;Randall & Goodbourn, 2008; Sharma et al., 2003). Activated IFN transcription factors translocate to the nucleus and activate IFN transcription (Biron, 2001). Secreted IFN binds to the IFN receptor and activates a JAK/STAT signalling pathway, upregulating the expression of a subset of genes that impede virus replication (Randall & Goodbourn, 2008). However, many viruses have evolved mechanisms to circumvent the IFN response (Blakqori et al., 2007;Jennings et al.,...

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Rac1 and PAK1 are upstream of IKK‐ε and TBK‐1 in the viral activation of interferon regulatory factor‐3

Cited by 117 publications

References 36 publications

Involvement of the IκB Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation

Involvement of the IκB Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation

The TAK1-JNK cascade is required for IRF3 function in the innate immune response

The cysteine protease domain of porcine reproductive and respiratory syndrome virus non-structural protein 2 antagonizes interferon regulatory factor 3 activation

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