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Updated: Jul 8, 2026
Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Identification of MAVS splicing variants that interfere with RIGI/MAVS pathway signaling
Sonya P Lad1, Guang Yang, David A Scott
1Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
Abstract:
The mitochondrial anti-viral signaling protein (MAVS), also known as CARDIF, IPS-1, KIAA1271 and VISA, is a mitochondria associated protein that regulates type I interferon production through coordinated activation of NF-kappaB and IRF3. The N-terminal CARD domain of MAVS interacts with RIGI helicase of upcapped RNA detection and the putative TRAF2 and TRAF6 binding motifs modulate protein interaction for NF-kappaB activation. MAVS is encoded by a single gene composed of 6 exons but is generally detected as multiple protein bands after separation by SDS-PAGE. In an effort to identify MAVS variants with diverse biological functions, we isolated three splicing variants and named them MAVS 1a (exon 2 deletion), 1b (exon 3 deletion) and 1c (exon 6 deletion), respectively. MAVS 1a and 1b, due to a frame shift by exon deletion, encode 131 and 124 aa residues, respectively. Except the first 39 aa residues encoded by exon 1, MAVS 1a does not share sequence homology with known proteins, it instead contains a putative TRAF2-binding motif and interacts with TRAF2 and RIP1. MAVS 1b shares the first 97 residues with wt MAVS and 27 aa residues of unknown protein. Unlike MAVS that activates both NF-kappaB and IRF3 pathways, expression of MAVS 1b selectively activates an IFNbeta but not an IL8 promoter. MAVS 1b interacts with RIP1 and FADD and exhibits anti-viral activity against VSV infection. This study uncovers MAVS splicing variants of diverse biological function.
Insights
Researchers discovered novel MAVS splicing variants with distinct biological functions. These variants, MAVS 1a and 1b, demonstrate altered signaling pathways and antiviral activities, expanding our understanding of innate immunity regulation.
Area of Science:
- Immunology
- Molecular Biology
- Virology
Background:
- Mitochondrial antiviral signaling protein (MAVS) is crucial for type I interferon production and innate immune responses.
- MAVS regulates antiviral signaling by activating NF-kappaB and IRF3 pathways.
- MAVS is encoded by a single gene but can exist as multiple protein bands due to post-transcriptional modifications.
Purpose of the Study:
- To identify and characterize novel MAVS splicing variants with diverse biological functions.
- To investigate the impact of exon deletions on MAVS protein structure and function.
- To explore the differential activation of signaling pathways by MAVS variants.
Main Methods:
- Isolation and characterization of three MAVS splicing variants (MAVS 1a, 1b, 1c) through exon deletion.
- Analysis of protein sequence homology and interaction domains.
- Assessment of NF-kappaB and IRF3 pathway activation using promoter assays.
- Evaluation of antiviral activity against Vesicular Stomatitis Virus (VSV) infection.
Main Results:
- MAVS 1a (exon 2 deletion) and MAVS 1b (exon 3 deletion) were identified as truncated variants with altered protein sequences.
- MAVS 1a interacts with TRAF2 and RIP1, while MAVS 1b interacts with RIP1 and FADD.
- MAVS 1b selectively activates the IFNbeta promoter but not the IL8 promoter, unlike wild-type MAVS.
- MAVS 1b exhibits significant antiviral activity against VSV infection.
Conclusions:
- The study successfully identified MAVS splicing variants with distinct functional properties.
- MAVS variants exhibit differential modulation of innate immune signaling pathways.
- These findings reveal novel mechanisms of antiviral defense and expand the functional repertoire of MAVS in innate immunity.
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