Identification of MAVS splicing variants that interfere with RIGI/MAVS pathway signaling☆

Lad, Sonya P.; Yang, Guang; Scott, David A.; Chao, Ta-Hsiang; Correia, Jean da Silva; Torre, Juan Carlos de la; Li, Erguang

doi:10.1016/j.molimm.2007.11.018

Cited by 49 publications

(41 citation statements)

References 38 publications

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“…These data from the present study and previous report (Lad et al, 2008) suggested that the C-terminal TM may be dispensable for MAVS signaling function.…”

Section: Discussionsupporting

confidence: 84%

“…In mammals, MAVS is encoded by a single gene composed of 6 exons, but three splicing variants are generated by exon deletion, with exon 2 deletion for MAVS1a, exon 3 deletion for MAVS 1b, and exon 6 deletion for MAVS 1c (Lad et al, 2008). In salmon, a mini-MAVS variant is also generated by exon deletion.…”

Section: Discussionmentioning

confidence: 99%

“…Although both MAVS1a and MAVS1b lack TM domain, MAVS variants exhibit diverse biological functions. MAVS 1a inhibits RIG-I and MAVS activity, whereas MAVS 1b displays antiviral activity against VSV infection, and selectively activates IFNβ promoter (Lad et al, 2008). In addition, the truncated variant miniMAVS interferes with IFN production induced by full-length MAVS (Brubaker et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…In mammals, three MAVS variants were isolated from human Hela 229 cells, and MAVS variants 1a and 1b containing uncharacterized sequences showed opposite effect on IFNβ expression, while variant 1c without the C-terminal TM had no activity on either NF-κB or IRF3 pathway (Lad et al, 2008); a miniMAVS, which was expressed from a second translational start site M142, was also identified in human cell lines, and the truncated variant without CARD domain interfered with IFN production induced by full-length MAVS (Brubaker et al, 2014). In teleost fish, MAVS orthologs have been reported from Japanese flounder (Paralichthys olivaceus) (Simora et al, 2010), salmon (Salmo salar) (Biacchesi et al, 2009;Lauksund et al, 2009), zebrafish (Danio rerio) (Biacchesi et al, 2009(Biacchesi et al, , 2012Xiong et al, 2012), carp (Cyprinus carpio) (Feng et al, 2011), grass carp (Ctenopharyngodon idella) (Su et al, 2011;Wan et al, 2013) and spotted green pufferfish (Tetraodon nigroviridis) (Xiang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

MAVS splicing variants contribute to the induction of interferon and interferon-stimulated genes mediated by RIG-I-like receptors

Chen

Zou

et al. 2015

Developmental & Comparative Immunology

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“…These data from the present study and previous report (Lad et al, 2008) suggested that the C-terminal TM may be dispensable for MAVS signaling function.…”

Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MAVS splicing variants contribute to the induction of interferon and interferon-stimulated genes mediated by RIG-I-like receptors

Chen

Zou

et al. 2015

Developmental & Comparative Immunology

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“…MAVS 1a strongly interacted with receptor-interacting protein 1 (RIP1), but had no activity on IFN b promoter, whereas MAVS 1b inducted IFN b promoter activity, even though showed weak interaction with RIP1. As a truncated variant without the TM domain, MAVS 1c was unable to promote NF-kB and IRF3 pathway [14].…”

Section: Introductionmentioning

confidence: 98%

Functions of the two zebrafish MAVS variants are opposite in the induction of IFN1 by targeting IRF7

et al. 2015

Fish & Shellfish Immunology

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Novel splice variants of human IKKε negatively regulate IKKε‐induced IRF3 and NF‐kB activation

et al. 2010

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The inhibitor of jB kinase e (IKKe) is pivotal for an efficient innate immune response to viral infections and has been recognized as breast cancer oncogene. The antiviral function of IKKe involves activation of the transcription factors IFN regulatory factor 3 (IRF3) and NF-jB, thus inducing the expression of type I IFN. Here, we have identified two novel splice variants of human IKKe, designated IKKe-sv1 and IKKe-sv2, respectively. Interestingly, RT-PCR revealed quantitatively different isoform expression in PBMC from different individuals. Moreover, we found cell type-and stimulus-specific protein expression of the various splice variants. Overexpression of full-length wt IKKe (IKKe-wt) leads to the activation of NF-jB-as well as IRF3-driven luciferase reporter genes. Although none of the splice variants activates IRF3, IKKe-sv1 still activates NF-jB, whereas IKKe-sv2 is also defective in NF-jB activation. Both splice variants form dimers with IKKe-wt and inhibit IKKe-wt-induced IRF3 signaling including the antiviral activity in a dominant-negative manner. The lack of IRF3 activation is likely caused by the failure of the splice variants to interact with the adapter proteins TANK, NAP1, and/or SINTBAD. Taken together, our data suggest alternative splicing as a novel regulatory mechanism suitable to shift the balance between different functions of IKKe.Key words: IFN . Innate immunity . NF-kB pathway . Protein/protein interactions . Signal transductionSupporting Information available online IntroductionViral infections are recognized by the innate immune system, which is essential for the subsequent initiation of adaptive immunity. Invading viruses are sensed by pattern-recognition receptors (PRR) recognizing pathogen-associated molecular patterns such as singleor double-stranded RNA. These PRR comprise TLR with endosomal/lysosomal localization like TLR3 and cytoplasmic receptors such as the retinoic acid-inducible protein I and melanoma differentiation-associated gene 5. Activation of these PRR engages intracellular signaling cascades leading to the secretion of type I IFN, which are important anti-viral cytokines ultimately facilitating viral clearance [1,2]. The signal transduction pathways leading to type I IFN expression involve activation of the serine/threonine kinases TANK-binding kinase 1 (TBK-1), also known as NF-kB activating kinase NAK [3], and inhibitor of kB kinase e (IKKe), also known as IKKi [4]. After virus infection, both kinases are activated and phosphorylate the transcription factor IFN regulatory factor 3 (IRF3), leading to homo-dimerization, translocation into the nucleus, and activation of promoters containing the IRF3 binding site termed IFN-stimulated response element [5,6]. For IRF3 activation after triggering of different PRR, the three related scaffold proteins NAP1, TANK, and SINTBAD are essential [7][8][9], whereas the use of a distinct scaffold protein depends on the respective stimulus activating the TBK1/IKKe pathway [10]. Ultimately, the formation of a multisubunit complex c...

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Identification of MAVS splicing variants that interfere with RIGI/MAVS pathway signaling☆

Cited by 49 publications

References 38 publications

MAVS splicing variants contribute to the induction of interferon and interferon-stimulated genes mediated by RIG-I-like receptors

MAVS splicing variants contribute to the induction of interferon and interferon-stimulated genes mediated by RIG-I-like receptors

Functions of the two zebrafish MAVS variants are opposite in the induction of IFN1 by targeting IRF7

Novel splice variants of human IKKε negatively regulate IKKε‐induced IRF3 and NF‐kB activation

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