Affinage

CARD19

Caspase recruitment domain-containing protein 19 · UniProt Q96LW7

Length
228 aa
Mass
25.6 kDa
Annotated
2026-06-09
10 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CARD19 (BinCARD-2) is the only detectable translated product of the C9orf89 locus and is an outer mitochondrial membrane protein that contributes to cristae architecture while modulating innate immune and tolerance signaling through its CARD domain (PMID:32763502, PMID:35406738). Mitochondrial targeting depends on its distal C-terminus and transmembrane domain rather than its CARD; at the OMM it interacts with the MICOS components MIC19, MIC25, and MIC60 and the associated proteins SAMM50 and MTX2, and its loss produces irregular cristae that phenocopy MICOS subunit depletion (PMID:35406738). The isolated CARD domain adopts a canonical fold with a cis-peptide bond and oxidized cysteines consistent with a redox-sensitive, membrane-localized protein (PMID:23633586). Functionally, CARD19 associates with MAVS to promote its oligomerization downstream of RIG-I, positively regulating RLR-driven IFN-β and IL-6 production (PMID:30795865), and it binds TAK1 to inhibit TAB2-mediated TAK1 ubiquitination, thereby restraining BCR/NF-κB signaling and shaping self-reactive B cell tolerance and lupus-like autoimmunity (PMID:36961449). An earlier model in which CARD19 binds BCL10 to suppress NF-κB activation reflects an overexpression artifact: endogenous CARD19 loss has no effect on BCL10-dependent NF-κB activation or MALT1 protease function in primary T cells (PMID:15637807, PMID:32763502), and a reported role in pyroptotic membrane rupture was likewise attributable to off-target disruption of the adjacent Ninj1 locus rather than to CARD19 itself (PMID:34648590).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2004 Medium

    The first functional hypothesis cast CARD19 as a CARD-dependent inhibitor of BCL10, addressing whether it tunes NF-κB signaling.

    Evidence Co-IP, mammalian two-hybrid, in vitro binding, and CARD residue mutagenesis in overexpression systems

    PMID:15637807

    Open questions at the time
    • Based on overexpression, not endogenous protein
    • No demonstration of endogenous BCL10 complex
    • Later refuted in primary T cells
  2. 2013 High

    Solving the CARD domain structure established its fold and revealed oxidized cysteines and a cis-peptide bond, hinting at redox sensitivity tied to subcellular environment.

    Evidence X-ray crystallography of native and selenomethionine double-mutant CARD domain at 1.4–1.58 Å

    PMID:23633586

    Open questions at the time
    • Structure of full-length membrane protein not determined
    • Functional consequence of cysteine oxidation not tested
    • No partner co-structure
  3. 2019 Medium

    CARD19 was assigned a positive role in antiviral signaling by promoting MAVS oligomerization, distinct from the inhibitory NF-κB model.

    Evidence Reciprocal Co-IP, siRNA knockdown, IFNB reporter, and VSV infection in A549 cells

    PMID:30795865

    Open questions at the time
    • Mechanism of how CARD19 drives MAVS oligomerization unresolved
    • Single lab/cell type
    • Not validated in primary cells or knockout
  4. 2020 High

    Endogenous-level analysis showed CARD19 is mitochondrial and dispensable for BCL10/NF-κB/MALT1 signaling, overturning the original overexpression-based model.

    Evidence Endogenous immunoblotting and confocal microscopy plus CARD19 KO in primary murine CD8+ T cells with NF-κB and MALT1 cleavage readouts

    PMID:32763502

    Open questions at the time
    • Did not define the actual mitochondrial function
    • Restricted to T cells
    • Mechanism of mitochondrial targeting not addressed
  5. 2021 High

    Two independent knockout lines resolved a contested role in pyroptosis, showing the lysis phenotype arose from off-target Ninj1 disruption, not CARD19.

    Evidence Comparison of Card19lxcn vs CRISPR Card19Null mice, RNA-seq, western blot, NINJ1 reconstitution, and Yersinia survival assays

    PMID:34648590

    Open questions at the time
    • Does not assign CARD19 a positive function
    • Cautions that prior gene-trap line is confounded
  6. 2022 High

    Localization and proteomics established CARD19's core cell-biological function as an OMM protein in the MICOS interactome required for normal cristae morphology.

    Evidence SIM/TEM/confocal, proteinase K protection, deletion mutagenesis, mass spectrometry of immunoprecipitates, and siRNA knockdown

    PMID:35406738

    Open questions at the time
    • Molecular role within MICOS (structural vs regulatory) unresolved
    • How cristae role connects to immune signaling unclear
    • Direct vs indirect MICOS contacts not dissected
  7. 2022 Medium

    An incompletely spliced isoform (BinCARD1) was implicated in IAV vRNP nuclear import and counter-regulated by ubiquitin-driven autophagic degradation, distinguishing isoform-specific functions.

    Evidence Co-IP, K103 ubiquitination and autophagy/degradation assays, mutagenesis, and IAV infection models

    PMID:36056146

    Open questions at the time
    • Pertains to a non-canonical isoform, not CARD19/BinCARD-2
    • Single lab
    • Endogenous isoform abundance unclear
  8. 2023 Medium

    CARD19 was shown to restrain TAK1 activation, linking it to B cell tolerance and protection from lupus-like autoimmunity.

    Evidence CARD19-TAK1 Co-IP, TAB2-mediated TAK1 ubiquitination assays, CARD19 KO mice, BCR signaling, RNA-seq, and a Bm12 SLE model

    PMID:36961449

    Open questions at the time
    • Mechanistic link between mitochondrial localization and TAK1 inhibition unresolved
    • Single lab
    • Direct vs indirect TAK1 regulation not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CARD19's outer-membrane MICOS/cristae role mechanistically connects to its CARD-mediated effects on MAVS-driven IFN-β and TAK1-dependent tolerance signaling remains unresolved.
  • No unified model linking cristae architecture to immune signaling
  • Whether MAVS and TAK1 effects require mitochondrial localization untested
  • Redox regulation of CARD function not functionally validated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0005198 structural molecule activity 1
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-168256 Immune System 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
BCL10MAVSMIC19MIC25MIC60MTX2SAMM50TAK1
Complex memberships
MICOS

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 BinCARD (CARD19) interacts with Bcl10 through its CARD domain, and this interaction suppresses Bcl10-induced NF-κB activation and Bcl10 phosphorylation. Mutations at conserved CARD residues Leu17 or Leu65 abolished both the inhibitory effect on NF-κB and on Bcl10 phosphorylation. Co-immunoprecipitation, in vitro binding, mammalian two-hybrid, immunostaining, and CARD domain mutagenesis FEBS letters Medium 15637807
2013 Crystal structures of the BinCARD (CARD19) CARD domain were solved to 1.58 Å (native) and 1.40 Å (selenomethionine double mutant), revealing a canonical CARD fold, a cis-peptide bond between Tyr39 and Pro40, and oxidation of all three cysteines, suggesting a potential redox-regulatory role consistent with mitochondrial localization of BinCARD-2. X-ray crystallography (MAD phasing with selenomethionine-substituted double mutant; space group P1) Acta crystallographica. Section D, Biological crystallography High 23633586
2019 BinCARD2 (CARD19) associates with MAVS and promotes MAVS oligomerization downstream of RIG-I, positively regulating RLR-mediated IFN-β production. Knockdown of BinCARD2 impaired MAVS oligomerization and reduced IFN-β and IL-6 induction after VSV infection, without affecting RIG-I/MAVS binding. Co-immunoprecipitation, siRNA knockdown, IFNB promoter reporter assay, VSV infection of A549 cells Biochemical and biophysical research communications Medium 30795865
2020 The only detectable translated product of C9orf89 is CARD19 (BinCARD-2, the properly spliced isoform); endogenous CARD19 localizes to mitochondria in primary cells. Loss of endogenous CARD19 had no discernible effect on Bcl10-dependent NF-κB activation, Malt1 protease function, or Bcl10 degradation after TCR engagement in primary murine CD8+ T cells, demonstrating that the previously reported NF-κB regulatory function reflects an overexpression artifact. Immunoblotting, confocal microscopy of endogenous CARD19, CARD19 knockout in primary murine CD8+ T cells, NF-κB reporter assays, Malt1 substrate cleavage assays Cellular immunology High 32763502
2021 A Card19-deficient mouse line (Card19lxcn) showed impaired macrophage cell lysis downstream of gasdermin D cleavage and increased susceptibility to Yersinia infection, but an independently generated CRISPR/Cas9 Card19Null mouse showed no such defect. RNA-seq and western blotting revealed that Card19lxcn macrophages have severely reduced NINJ1 expression due to off-target disruption of the adjacent Ninj1 locus; reconstitution of Ninj1 rescued cell lysis, demonstrating that CARD19 itself is not required for pyroptotic plasma membrane rupture. Two independent KO mouse lines, RNA-seq, western blotting, NINJ1 reconstitution experiments, Yersinia infection survival assays PLoS pathogens High 34648590
2022 CARD19 is specifically localized to the outer mitochondrial membrane (OMM); both the distal C-terminus and transmembrane domain are required for mitochondrial targeting, whereas the CARD domain is not. Mass spectrometry of CARD19 immunoprecipitates identified interactions with MICOS components MIC19, MIC25, and MIC60, and MICOS-interacting proteins SAMM50 and MTX2. These interactions are partly dependent on a properly folded CARD. Loss of CARD19 correlates with irregular cristae morphology, phenocopying silencing of MICOS subunits. SIM, TEM, confocal microscopy, proteinase K protection assay, deletion mutagenesis, mass spectrometry of immunoprecipitates, siRNA knockdown Cells High 35406738
2022 IAV leverages BinCARD1 (an incompletely spliced isoform of CARD19) to promote nuclear import of the viral ribonucleoprotein (vRNP) complex: BinCARD1 interacts with viral NP and facilitates its binding to importin α7. Concurrently, BinCARD1 is polyubiquitinated at K103 via Lys63-linked chains, which are recognized by the TBK1-p62 axis for autophagic degradation, limiting its pro-viral activity. Co-immunoprecipitation, ubiquitination assays, autophagy/degradation assays, mutagenesis (K103), siRNA knockdown, IAV infection models Cellular & molecular immunology Medium 36056146
2023 CARD19 interacts with TAK1 and inhibits TAB2-mediated TAK1 ubiquitination and activation. In self-reactive B cells, CARD19 deficiency increases BCR/TAK1-mediated NF-κB activation, leading to elevated expression of Egr2/3 and E3 ubiquitin ligases c-Cbl/Cbl-b, which enhance B cell tolerance. CARD19 deficiency enhanced clonal deletion, receptor editing, and anergy of self-reactive B cells and prevented experimental SLE in a Bm12 model. Co-immunoprecipitation (CARD19-TAK1), ubiquitination assays (TAB2-mediated TAK1 ubiquitination), CARD19 knockout mice, BCR signaling assays, RNA sequencing, Bm12-induced SLE model Journal of immunology Medium 36961449

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Influenza A virus use of BinCARD1 to facilitate the binding of viral NP to importin α7 is counteracted by TBK1-p62 axis-mediated autophagy. Cellular & molecular immunology 37 36056146
2021 Genetic targeting of Card19 is linked to disrupted NINJ1 expression, impaired cell lysis, and increased susceptibility to Yersinia infection. PLoS pathogens 35 34648590
2004 Inhibition of Bcl10-mediated activation of NF-kappa B by BinCARD, a Bcl10-interacting CARD protein. FEBS letters 17 15637807
2013 The structure of the caspase recruitment domain of BinCARD reveals that all three cysteines can be oxidized. Acta crystallographica. Section D, Biological crystallography 12 23633586
2019 BinCARD2 as a positive regulator of interferon response in innate immunity. Biochemical and biophysical research communications 9 30795865
2022 CARD19 Interacts with Mitochondrial Contact Site and Cristae Organizing System Constituent Proteins and Regulates Cristae Morphology. Cells 8 35406738
2020 CARD19, the protein formerly known as BinCARD, is a mitochondrial protein that does not regulate Bcl10-dependent NF-κB activation after TCR engagement. Cellular immunology 6 32763502
2023 Indirect CRISPR screening with photoconversion revealed key factors of drug resistance with cell-cell interactions. Communications biology 5 37264057
2022 A Bayesian network structure learning approach to identify genes associated with stress in spleens of chickens. Scientific reports 4 35523843
2023 CARD19, a Novel Regulator of the TAK1/NF-κB Pathway in Self-Reactive B Cells. Journal of immunology (Baltimore, Md. : 1950) 2 36961449

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