MYC is not an ordinary transcription factor. Beyond directly activating target genes, it operates as a global amplifier of all active genes, boosting both transcriptional activators and the core transcriptional machinery itself. Because even modest changes in MYC protein levels can shift cellular behavior or trigger oncogenesis, the protein is regulated at nearly every conceivable level: multiple promoters and cis-regulatory elements control its transcription, RNA-binding proteins and microRNAs shape its transcript stability and translation, and post-translational modifications such as phosphorylation, acetylation, and ubiquitination tune its stability and activity. Canonical degradation proceeds through the proteasome, but recent work has revealed additional routes, including selective autophagy in keratinocytes—a mechanism since observed in colorectal cancer—and K63-linked polyubiquitination by TRAF6 in myeloid cells, which counters an activating acetylation mark and prevents leukemogenesis.

The stakes of getting MYC regulation wrong are enormous. Unchecked MYC signaling drives uncontrolled proliferation and metabolic reprogramming, undermines tumor-suppressive mechanisms, and promotes genomic instability. Hematological malignancies of B-cells, T-cells, plasma cells, and myeloid lineages are frequently driven by or associated with MYC dysregulation, while epithelial cancers—including cutaneous squamous cell carcinoma, its precursor actinic keratosis, and carcinomas of the head and neck, lung, esophagus, and colon—also bear its fingerprint. Within the immune system, MYC directs the balance between self-renewal and differentiation in hematopoietic stem cells, guides B- and T-cell development, sustains myeloid populations, and maintains the epithelial barriers that form the body’s first line of defense against allergens and microbes.

The CBM complexes, meanwhile, are built around four paralogs of the CARD-CC family: CARD9, CARD10, CARD11, and CARD14. Each paralog occupies a distinct cellular niche—CARD9 in myeloid cells, CARD10 in endothelia and solid organs, CARD11 in lymphoid cells, and CARD14 in epidermal and mucosal epithelia—yet all can assemble supramolecular signalosomes with BCL10 and MALT1. In their inactive state, CARD-CC proteins are locked in an autoinhibited conformation; upstream receptors relieve this inhibition through post-translational modifications such as phosphorylation, and many disease-associated gain-of-function mutations bypass this control entirely by altering residues within the autoinhibitory regions. Once activated, the complexes recruit TRAF6-mediated K63-linked polyubiquitination to ignite NF-κB signaling, while MALT1’s protease activity cleaves deubiquitinases that would otherwise dismantle the polyubiquitin chains, potentiating the inflammatory output.

The clearest evidence for CBM-MYC crosstalk comes from CARD11, the paralog best known for its role in T-cell and B-cell receptor signaling. In mantle cell lymphoma, BCR-driven CARD11-MALT1 signaling sustains MYC activity by reducing its proteasomal degradation, and the proliferation and survival of MCL cell lines prove dependent on this pathway. MYC levels also drop in splenocytes carrying catalytically inactive MALT1, showing that the mechanism operates in untransformed B-cells as well. Yet the relationship is not simply additive: in diffuse large B-cell lymphoma, gain-of-function CARD11 mutants appear to act as a second hit alongside constitutively expressed MYC, hinting that the two pathways are independent but complementary contributors to lymphomagenesis.

Regulatory T cells tell a different story. Rosenbaum and colleagues demonstrated that CARD11-MYC signaling induces Myc mRNA expression in Tregs, enhancing their proliferation and the mitochondrial metabolism these cells preferentially use. Unlike in B-cells, CBM signaling in Tregs does not affect MYC proteasomal degradation, and MALT1-MYC signaling protects mice against fatal autoimmune disease. Strikingly, mice with protease-dead MALT1 resemble mice lacking MYC specifically in Tregs, supporting the idea that CARD11-MYC operates as a separate but cooperative arm alongside CARD11-NF-κB in regulatory T-cell biology. Because Treg defects associated with CARD11 deficiency are not fully rescued by NF-κB restoration alone, MYC may fill a crucial gap in explaining these phenotypes. Effector T-cells depend on both proteins too—MYC for metabolic reprogramming upon activation, CARD11 for cytokine expression and proliferation—though MALT1 paracaspase activity did not appear to influence MYC mRNA or mitochondrial metabolism in conventional CD4-positive T-cells, leaving open questions about how CARD11 might regulate MYC in these cells.

In the skin, CARD14 has emerged as a direct physical regulator of MYC with profound consequences for barrier integrity. After linking the CARD14 R820W variant to reduced epidermal filaggrin expression in children with atopic dermatitis, DeVore’s group found that keratinocytes carrying the variant showed prominently decreased MYC transcriptional signatures despite only subtle changes in NF-κB signaling. CARD14 did not alter MYC expression or proteasomal degradation; instead, it physically interacted with MYC in a manner dependent on variant and activation status. Activation of wild-type CARD14 promoted MYC dissociation from the complex, nuclear localization, and transcriptional activity, whereas the R820W variant and MALT1 inhibition kept MYC tethered to the CBM and funneled it toward autophagic degradation. Dysregulated CARD14-MYC signaling impaired keratinocyte proliferation, differentiation, and barrier function, and skin expressing psoriasis-associated gain-of-function CARD14 mutants displayed both elevated MYC signatures and classic psoriatic features such as epidermal hyperproliferation and parakeratosis. Most recently, CARD14 was shown to drive osteoclast differentiation in a MYC-dependent fashion, binding MYC directly, enhancing its stability, and promoting its nuclear translation while simultaneously activating NF-κB and MAPK pathways.

CARD9 and CARD10 remain more speculative territory. CARD9, the myeloid paralog essential for antifungal immunity, may actually suppress MYC: pro-inflammatory M1 macrophages, which require CARD9 signaling, downregulate MYC, whereas CARD9 deficiency promotes polarization toward M2 macrophages that depend on MYC for activation and even carry it as a cellular marker. This antagonism suggests that strong CARD9 signaling may suppress MYC to drive M1 polarization, while reduced signaling disinhibits MYC and permits M2 polarization—though direct studies are still needed. In myeloid progenitors, TLR2 signaling through MyD88 and TRAF6 suppresses MYC and blocks progression to acute myeloid leukemia, and because TLR2-MyD88 signaling can also activate the CARD9 CBM complex, which likewise employs TRAF6, CARD9 could plausibly contribute to this tumor-suppressive MYC downregulation. CARD10, expressed in endothelia, smooth muscle, and various epithelia, has never been directly tested for MYC regulation, but CARD10 knockdown reduced β-catenin-mediated MYC expression and blunted invasion and proliferation of bladder carcinoma cells, with β-catenin overexpression rescuing both—hinting at a possible CARD10-β-catenin-MYC axis. Notably, many cancer-associated CARD10 mutations do not affect NF-κB signaling at all, raising the possibility that MYC or other pathways carry the functional impact instead.

The authors propose a unifying structural clue: CARD9 lacks the membrane-associated guanylate kinase (MAGUK) domain that is predicted in silico to bind MYC, which could explain why it suppresses rather than promotes MYC signaling, and why the MAGUK-deficient splice variant CARD14sh might behave similarly. Whether the MAGUK domain is genuinely required for MYC promotion remains an open experimental question. What is already clear is that CBM-dependent MYC regulation is cell-type and paralog-specific—CARD11 affects MYC proteasomal degradation in B-cells but not Tregs, and CARD11 but not CARD14 influences MYC transcription—so future studies must map which layers of MYC control each complex touches, from transcript stability and translation to post-translational modification by TRAF6-mediated ubiquitination.

The broader implication is that CBM complexes coordinate two parallel output channels: the canonical NF-κB arm and the newly recognized MYC arm, working in functional complementarity. B-cell and Treg development depend partially on both CARD11-MYC and CARD11-NF-κB signaling; the physical skin barrier built through CARD14-MYC complements the chemical barrier of antimicrobial peptides and cytokines driven by CARD14-NF-κB; and both pathways promote osteoclastogenesis. This dual-channel architecture may finally explain the pleiotropic presentations of CBM-associated diseases, from combined immunodeficiency and atopy syndromes such as CADINS and BENTA to psoriasis, atopic dermatitis, and lymphoid malignancies. For drug developers, the message is significant: therapies targeting MALT1 protease activity or CBM assembly are already in clinical pipelines, and understanding how these interventions ripple through MYC-dependent programs could reveal why some patients respond differently than expected—and open entirely new therapeutic angles for MYC-driven cancers and inflammatory diseases alike.

Subject of Research: Regulation of the MYC transcription factor by CARD-CC-BCL10-MALT1 signaling complexes

Article Title: MYC is in the CARDs: CBM complexes coordinate immune and MYC-dependent cellular function

Article References: DeVore, S. B., & Khurana Hershey, G. K. (2025). MYC is in the CARDs: CBM complexes coordinate immune and MYC-dependent cellular function. Frontiers in Molecular Medicine, 5, Article 1731823. https://doi.org/10.3389/fmmed.2025.1731823

Image Credits: AI Generated

DOI: 10.3389/fmmed.2025.1731823

Keywords: MYC, CBM complex, CARD11, CARD14, CARD9, CARD10, NF-κB, MALT1, BCL10, immune signaling, cancer, keratinocytes