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rig-i-mavs-pathway

Properties1
aliasesRLR pathway, RIG-I-like receptor signaling, RIG-I-MAVS signaling, RLR signaling, MAVS pathway, innate RNA-sensing pathway

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RIG-I/MAVS innate RNA-sensing pathway

The RIG-I/MAVS pathway (also called the RLR — RIG-I-like receptor — pathway) is the cytosolic innate immune sensing circuit for intracellular RNA. Three DExD/H-box RNA helicases — RIG-I (DDX58), MDA5 (IFIH1), and LGP2 (DHX58) — patrol the cytoplasm for foreign or aberrant RNA signatures. Detection activates the outer mitochondrial membrane (OMM) adaptor MAVS, which polymerizes into a self-propagating prion-like signalosome, recruits TBK1 and IKKε, and phosphorylates the transcription factors IRF3 and IRF7 to drive type I interferon (IFN-I) production. In aging, this pathway is engaged not only by viral infection but by endogenous danger signals: mitochondrial dsRNA (mt-dsRNA) that leaks from dysfunctional mitochondria, and retrotransposon RNA (LINE-1, ERV) reactivated by epigenetic derepression. Both sources feed chronic low-level MAVS activation that amplifies the inflammaging program.

Naming note: This page is the canonical [[rig-i-mavs-pathway]] wikilink target and covers the pathway. Individual protein pages exist for [[mavs]], [[tbk1]], [[irf3]], and [[ikbke]]. Pages for [[rig-i]], [[mda5]], [[lgp2]], and [[irf7]] are implicit stubs pending seeding. The companion DNA-sensor page is [[cgas-sting]]; both converge on [[type-i-interferon-signaling]].

Sensor specificity table

The three RLR family members recognize overlapping but distinct RNA features:

SensorGeneLigand preferenceMinimum lengthKey structural featureAging-relevant endogenous ligand
RIG-IDDX585′-triphosphate (5′-ppp) ssRNA; short dsRNA (<300 bp)~10–20 bpC-terminal repressor domain (RD) maintains autoinhibited state; 5′-ppp binding releases autoinhibitionmt-ssRNA with 5′-ppp; retroelement RNA
MDA5IFIH1Long dsRNA (>300 bp); lacks 5′-ppp requirement~300–1000 bp+Cooperative filament assembly along dsRNA; no autoinhibitory domainmt-dsRNA (long, double-stranded mitochondrial transcript duplex) 1
LGP2DHX58dsRNA (broad); no CARD domains—Lacks CARD signaling domains; regulates RIG-I and MDA5 activityModulatory role only; no direct signaling

Both RIG-I and MDA5 carry two CARD (caspase activation and recruitment) domains at their N-terminus. LGP2 lacks CARDs and acts as a regulatory co-factor: it inhibits RIG-I by competing for RNA substrates at low ligand concentrations, and enhances MDA5 filament assembly at higher concentrations 2.

Pathway architecture

Step 1: RNA detection and sensor activation

RIG-I is maintained in an autoinhibited conformation by its C-terminal regulatory domain (CTD/RD), which folds back to mask the N-terminal CARDs. Binding of 5′-ppp dsRNA to the CTD releases autoinhibition, exposing the CARDs. K63-linked polyubiquitin chains (assembled by TRIM25 and RIPLET on the CARDs) stabilize the active conformation and facilitate downstream MAVS engagement 3.

MDA5 assembles cooperatively into filaments along long dsRNA. Filament formation is cooperative and ATP-hydrolysis-dependent: MDA5 monomers stack along dsRNA, and the assembled filament presents CARDs on its surface for MAVS interaction. The cooperative geometry means MDA5 is especially sensitive to long duplex RNA — the kind generated by bidirectional transcription of mitochondrial genes.

Step 2: MAVS polymerization — the prion-like signalosome

mavs (Mitochondrial Antiviral Signaling protein; also known as IPS-1/VISA/CARDIF) is a single-pass transmembrane protein tethered to the outer mitochondrial membrane (OMM) via its C-terminal transmembrane domain 4. Its N-terminal CARD interacts with the CARDs of activated RIG-I or MDA5 complexes via CARD-CARD homotypic interactions.

The key mechanistic discovery of Hou et al. (2011): RIG-I — in the presence of K63-polyubiquitin — catalyzes the conversion of OMM-anchored MAVS from a monomeric state into self-propagating prion-like aggregates 3. These fibrillar aggregates:

  1. Robustly activate IRF3 (verified: Peak I Sumo-MAVS fibrils activated IRF3 in cell-free mitochondrial fractions at concentrations as low as 16 ng/ml 3)
  2. Self-propagate — recombinant MAVS fibrils seeded conversion of naive MAVS in cell-free mitochondrial fractions; ~1 ng PK-MAVS converted ~16 ng endogenous MAVS into aggregates within 30 min
  3. Are irreversible under physiological conditions (providing signal amplification and memory)

The OMM localization is functionally required: MAVS mislocalized to the plasma membrane (CAAX sequence) or ER (VAMP-2 targeting sequence) markedly loses signaling activity 4. unsourced — the peroxisome-MAVS mislocalization claim (Dixit 2010) requires a separate citation not yet on this page. PINK1-mediated mitophagy terminates MAVS signaling by degrading polymerized MAVS along with damaged mitochondria — providing a homeostatic brake that links mitophagy competency to innate immune tone (see pink1-parkin-pathway).

Step 3: TBK1/IKKε recruitment and IRF3/IRF7 phosphorylation

MAVS aggregates serve as a scaffold, recruiting downstream kinase complexes:

  • tbk1 (TANK-Binding Kinase 1) and ikbke (IKKε/IKKi) are recruited to the MAVS signalosome via adaptor proteins (TRAF2, TRAF5, TRAF6, TANK, SINTBAD)
  • TBK1 and IKKε phosphorylate irf3 at Ser386/Ser396 → IRF3 dimerization → nuclear translocation → IFNB1 transcription
  • irf7, expressed at low basal levels but strongly induced by IFN-I feedback, drives bulk IFNA gene transcription — amplifying the response
  • TBK1/IKKε also activate nf-kb via IκB kinase activity → pro-inflammatory cytokines (IL-6, TNF-α, IL-1β, CXCL10) that contribute to SASP
StepKey moleculesOutput
RNA sensingRIG-I (5′-ppp RNA) / MDA5 (long dsRNA)Sensor activation
CARD-CARD interactionRIG-I/MDA5 CARDs ↔ MAVS CARDMAVS recruitment
Prion-like polymerizationMAVS filaments on OMM (K63-Ub catalyzed)Signalosome assembly
Kinase recruitmentTBK1, IKKε via TRAF adaptorsIRF3/IRF7 phosphorylation
TranscriptionIRF3/IRF7 → ISRE; NF-κB → κB sitesIFN-I + pro-inflammatory cytokines
AmplificationSecreted IFN-α/β → IFNAR → JAK-STAT → ISGstype-i-interferon-signaling

Aging context

Mt-dsRNA leakage arm: linking mitochondrial dysfunction to innate immunity

The most mechanistically direct link between the mitochondrial-dysfunction hallmark and the RIG-I/MAVS pathway is through mitochondrial dsRNA (mt-dsRNA). Human mitochondrial DNA is transcribed from both strands, and several regions generate long complementary RNA pairs that form dsRNA duplexes — the canonical ligand for MDA5. Normally, the mitochondrial RNA degradosome (SUV3 helicase + PNPASE nuclease) degrades these aberrant duplexes within the mitochondrial matrix.

Dhir et al. (2018) demonstrated that genetic inactivation of SUV3 or PNPASE causes accumulation of mt-dsRNA that escapes to the cytoplasm, engaging MDA5 and triggering IFN-I production through MAVS 1. Critically, patients with biallelic PNPT1 mutations (encoding PNPase) showed elevated ISG scores in blood — directly linking mt-dsRNA degradosome deficiency to IFN-I activation in humans. Zhang et al. (2026) extended this to the aging context: SEC61A1, a protein regulating ER-mitochondria contact sites, modulates mt-dsRNA synthesis; SEC61A1 accumulation in aged mouse cortex elevated mt-dsRNA and activated the MAVS pathway; MAVS ablation in aged wild-type mice reduced cognitive decline 5. needs-replication — Zhang 2026 is a single study in aged mice; mechanism requires replication in human aging models.

Victorelli et al. (2025) closed the loop to cellular senescence: cytosolic mtRNA accumulates in senescent cells, activating RIG-I and MDA5, driving MAVS aggregation and SASP induction 6. BAX/BAK channel the mtRNA cytosolic leakage via mitochondrial outer membrane permeabilization (miMOMP); their genetic deletion reduces SASP in cell culture and in a mouse FFC-diet model of metabolic dysfunction-associated steatohepatitis (MASH). This establishes mt-dsRNA → RIG-I/MDA5 → MAVS as a direct driver of the innate immune component of SASP — distinct from the cGAS-STING (DNA-sensing) arm, though both arms converge on TBK1/IRF3 and both are activated in senescent cells.

DimensionStatus
Pathway conserved in humans?yes — Dhir 2018 demonstrated in human cell lines + PNPT1 patient cohort
mt-dsRNA leakage in aged human tissues?partial — indirect via ISG signatures; direct mt-dsRNA quantification in aged human tissue limited
Causal for inflammaging?partial — MAVS ablation rescues cognitive decline in aged mice (Zhang 2026); not yet tested in humans

Retroelement RNA arm: linking epigenetic derepression to innate RNA sensing

LINE-1 (L1) retrotransposons are derepressed with aging via heterochromatin loss (epigenetic-alterations hallmark). LINE-1 elements produce RNA species including the structured RNA that functions as RIG-I ligand when 5′-triphosphate modifications are present. Endogenous retroviruses (ERVs) generate dsRNA from convergent transcription — prime MDA5 ligands.

This arm connects epigenetic aging to innate immune activation through the RNA-sensing route, complementing the cGAS-STING pathway’s sensing of reverse-transcribed LINE-1 cDNA. no-mechanism — the specific molecular features of LINE-1/ERV RNA that activate RIG-I vs. MDA5 vs. TLR3 in aged cells are not yet fully characterized in a primary aging context (most data from antiviral and cancer-immunology settings). needs-replication — direct evidence for LINE-1 RNA → RIG-I/MAVS activation in naturally aged human tissues is not yet established; inferred from the broader retrotransposon-IFN-I literature (see type-i-interferon-signaling).

Convergence with the cGAS-STING pathway

The cGAS-STING pathway (DNA-sensing) and the RIG-I/MAVS pathway (RNA-sensing) are parallel innate immune arms both active in aged and senescent cells, both feeding into TBK1 → IRF3/IRF7 → IFN-I. Their relationship in aging:

FeaturecGAS-STINGRIG-I/MAVS
Primary liganddsDNA (cytosolic)dsRNA / 5′-ppp ssRNA (cytosolic)
Aging endogenous sourcemtDNA leak, CCFs, LINE-1 cDNAmt-dsRNA leak, LINE-1/ERV RNA
Adaptor localizationER membrane (STING)Outer mitochondrial membrane (MAVS)
Kinase relayTBK1 → IRF3TBK1/IKKε → IRF3/IRF7
SASP contributionYes (Glück 2017)Yes (Victorelli 2025)
Druggable nodeSTING (H-151, C-178, preclinical)MAVS polymerization / RIG-I CARDs (no clinical agent)

Both pathways can be activated simultaneously in senescent cells. Cross-talk exists: cGAS-STING can prime NLRP3 inflammasome (via NF-κB) and amplify pro-IL-1β precursor expression that is then processed by the inflammasome (see nlrp3-inflammasome).

Therapeutic angles

No clinical drug inhibits the RIG-I/MAVS pathway for aging indications. Druggability assessment:

  • MAVS polymerization — the prion-like aggregation mechanism theoretically offers a therapeutic target (block CARD-CARD interaction or K63-ubiquitin scaffold), but no advanced probe has been reported; druggability-tier: 3 (predicted druggable, no clinical agent).
  • TBK1/IKKε inhibition — several TBK1 inhibitors exist (e.g., BX795; GSK8612 for selectivity); none tested for aging-specific IFN-I suppression in humans. TBK1 is also required for mitophagy (via ULK1 phosphorylation) — inhibition carries risk of impairing mitochondrial quality control. See tbk1.
  • STING inhibitors — act downstream of both cGAS-STING and MAVS (both feed into the shared TBK1/IRF3 arm, but STING acts between cGAS and TBK1; STING inhibitors do NOT block MAVS → TBK1). Therefore STING inhibitors preferentially suppress the DNA-sensing arm; suppressing MAVS requires a separate target.
  • JAK1/TYK2 inhibitors (ruxolitinib, baricitinib) — suppress the downstream IFNAR → JAK-STAT signaling arm, not IFN-I production itself. Relevant for dampening ISG-mediated inflammatory burden in aging. See jak-stat-pathway and type-i-interferon-signaling.
  • PINK1/Parkin mitophagy enhancement — by clearing damaged mitochondria before mt-dsRNA leakage, mitophagy activators (urolithin A; see pink1-parkin-pathway) may indirectly reduce MAVS activation. This is a preventive rather than suppressive strategy.

long-term-unknown — no RIG-I/MAVS-targeted intervention has reached clinical evaluation for aging indications. Safety concern: suppressing RIG-I/MAVS signaling impairs antiviral immunity; the aged host is already immunocompromised.

  • mitochondrial-rna-leakage — aging-context synthesis page anchoring the mtRNA-MAVS axis as a mechanistic bridge from mitochondrial-dysfunction → cellular-senescence hallmarks; aggregates the 3-lab convergence (Victorelli 2025, López-Polo 2024, Zhang 2026) and intervention landscape (BAX/BAK inhibition, PNPase augmentation, shared amlexanox / jak1 handles)
  • cgas-sting — parallel cytosolic nucleic acid sensing arm; both converge on TBK1/IRF3; both activated in senescent cells by mitochondria-derived ligands; neither is fully redundant (DNA vs. RNA sensing, ER vs. OMM adaptors)
  • type-i-interferon-signaling — direct downstream; RIG-I/MAVS-generated IFN-I signals through IFNAR → JAK1/TYK2 → ISGF3 to induce interferon-stimulated genes
  • nlrp3-inflammasome — parallel innate immune arm; RIG-I signaling can activate NLRP3 via NF-κB-dependent IL-1β precursor synthesis; synergistic rather than redundant in aged cells
  • pink1-parkin-pathway — mitophagy provides the primary homeostatic control over mt-dsRNA leakage; MAVS aggregates are degraded along with cleared mitochondria; PINK1 also directly phosphorylates MAVS unsourced (PINK1-MAVS direct interaction; cite primary structural study)
  • nf-kb — parallel transcription factor arm; TBK1/IKKε activates both IRF3 (IFN-I arm) and IKKβ/NF-κB (pro-inflammatory cytokine arm)
  • mitochondrial-dynamics — MAVS function is tied to mitochondrial network state; MAVS signaling is enhanced when mitochondria are hyperfused (connected network), as MAVS aggregates propagate along the OMM; mitochondrial fragmentation (DRP1 activation) limits propagation unsourced (cite Chen 2013 or equivalent for mitochondrial fusion/MAVS coupling)
  • dna-damage-response — genomic instability generates the micronuclei and chromosomal fragments that activate cGAS-STING; the DNA-damage milieu also induces retroelement derepression that provides RIG-I/MAVS ligands

Limitations and knowledge gaps

  • Reactome ID R-HSA-168928 confirmed (display name: “DDX58/IFIH1-mediated induction of interferon-alpha/beta”; five-star curation status; last updated 2023-09-13). KEGG ID hsa04622 confirmed (RIG-I-like receptor signaling pathway — Homo sapiens). WikiPathways ID not identified. needs-canonical-id
  • mt-dsRNA aging data in humans: the clearest human data (Dhir 2018) come from PNPT1-mutation patients — a monogenic disease model, not physiological aging. Whether the mt-dsRNA degradosome declines with normal aging in humans at the level sufficient to activate MDA5 is not directly demonstrated. needs-replication
  • RIG-I vs. MDA5 aging specificity: Victorelli 2025 implicates both RIG-I and MDA5 in SASP, but whether they play non-redundant roles or one dominates in specific cell types and aged tissues is unknown. no-mechanism
  • MAVS prion propagation in aging: the prion-like MAVS polymerization model (Hou 2011) was demonstrated in cell lines with overexpressed MAVS or recombinant protein. Whether endogenous MAVS undergoes self-propagating polymerization at physiological concentrations during chronic low-level aging activation (rather than acute viral infection) is not established. needs-replication
  • Therapeutic window: suppressing RIG-I/MAVS in aged individuals to reduce inflammaging risks impairing antiviral defense — already compromised by immunosenescence. No dose-response or intermittent-dosing strategy has been characterized for this pathway in aging. dose-response-unclear
  • LGP2 aging role: LGP2 (DHX58) is the regulatory member of the RLR family; its expression and activity changes with age have not been characterized. Given its complex modulatory role (inhibitory at low, facilitative at high RNA doses), age-related LGP2 changes could shift the RIG-I/MDA5 activation threshold. unsourced
  • Intercellular propagation: whether MAVS signaling spreads between cells in aged tissues (analogous to cGAS-STING spreading via cGAMP transfer through gap junctions) has not been studied. no-mechanism

Footnotes

Footnotes

  1. doi:10.1038/s41586-018-0363-0 · Dhir A, Dhir S, Borowski LS et al. · Nature 2018 · in-vitro + human genetics · loss of mitochondrial RNA degradosome enzymes SUV3 + PNPASE causes mt-dsRNA cytoplasmic escape → MDA5 activation → type I IFN via MAVS; PNPT1-mutation patients show elevated blood ISG scores; mt-dsRNA visualized by dsRNA-specific antibody (J2) in SUV3-depleted cells · model: HeLa cells + 293 cells + primary fibroblasts from 4 PNPT1-mutation patients (ISG upregulation measured in peripheral blood); hepatocyte-specific PNPase KO mice · archive: downloaded (green OA) · PMID: 30046113 · cited ~590 times (FWCI 26.6; citation percentile 100) ↩ ↩2

  2. doi:10.3389/fimmu.2014.00342 · Reikine S, Nguyen JB, Modis Y · Frontiers in Immunology 2014 · review · pattern recognition mechanisms of RIG-I and MDA5; cooperative MDA5 filament assembly; LGP2 dual regulatory role (competitive inhibitor of RIG-I at low ligand; facilitates MDA5 filament assembly at higher doses); CARD-CARD signaling architecture · archive: not checked · cited ~400 times ↩

  3. doi:10.1016/j.cell.2011.06.041 · Hou F, Sun L, Zheng H, Skaug B, Jiang Q-X, Chen ZJ · Cell 2011 · in-vitro + biochemical · MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response; RIG-I + K63-polyubiquitin catalyzes MAVS conversion to fibrillar aggregates; MAVS fibrils activate IRF3 and propagate signal by converting naive MAVS; aggregate formation requires the CARD domain · model: HEK293T cells + cell-free mitochondrial fraction + purified recombinant proteins · archive: downloaded (bronze OA) · cited >800 times ↩ ↩2 ↩3

  4. doi:10.1016/j.cell.2005.08.012 · Seth RB, Sun L, Ea C-K, Chen ZJ · Cell 2005 · in-vitro · discovery of MAVS (Mitochondrial Antiviral Signaling protein; also IPS-1/VISA/CARDIF); demonstrated OMM localization via C-terminal TM domain is required for antiviral signaling (mislocalization to plasma membrane via CAAX or ER via VAMP-2 sequence markedly reduced activity; Bcl-2/Bcl-xL TM replacements maintaining mitochondrial localization preserved activity); CARD-CARD interaction with RIG-I established; NF-κB and IRF3 activation confirmed downstream of MAVS · model: HEK293 cells + multiple human cell lines (Jurkat, U937, Huh7, A549, HeLa) · archive: downloaded (bronze OA) ↩ ↩2

  5. doi:10.1038/s41422-026-01224-w · Zhang L, Li X, Luo H et al. · Cell Research 2026 · in-vivo + human samples · SEC61A1 accumulates in aged mouse cortex and regulates ER-mitochondria contacts affecting mt-dsRNA synthesis; elevated mt-dsRNA activates MAVS-mediated innate immune signaling in aged brains and Alzheimer’s disease tissue; Mavs ablation alleviates cognitive decline in naturally aging wild-type mice; overexpressing Sec61a1 induces cognitive decline in young mice · model: aged C57BL/6 mice + Alzheimer’s disease patient samples (Sec61a1 and mt-dsRNA pathology confirmed) · archive: not in archive · PMID: 41692872 · very recent (2026); treat as preliminary needs-replication ↩

  6. doi:10.1038/s41467-025-66159-z · Victorelli S, Eppard M, Martini H et al. · Nature Communications 2025 · in-vitro + in-vivo · cytosolic mtRNA accumulates in senescent cells and activates RIG-I and MDA5 → MAVS aggregation → SASP induction; BAX/BAK (miMOMP) regulate mtRNA cytosolic leakage; BAX/BAK double-KO (CRISPR) reduces SASP in vitro; hepatocyte-specific Bax/Bak deletion reduces SASP and liver inflammation in FFC-diet MASH mice · model: MRC5 and IMR90 human fibroblasts (IR-induced and replicative senescence); Bax-/- Bakfl/fl + AAV8-TBG-Cre FFC-diet mice · archive: gold OA; PDF downloaded · PMID: 41398033 · very recent (2025); treat as preliminary pending replication needs-replication ↩

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