VGLL3

VGLL3 is a transcriptional cofactor that partners with TEAD family transcription factors to regulate gene expression programs controlling inflammation, fibrosis, myogenesis, adipogenesis, and immune checkpoint signaling. VGLL3 binds TEAD1, TEAD3, and TEAD4 via a conserved Tondu motif and activates a Hippo pathway negative-feedback loop by inducing LATS2 and AMOTL2, thereby inactivating YAP/TAZ (PMID:32385107, PMID:31138678); it also forms a TEAD1–RUNX1/3 complex to drive PD-L1/PD-L2 expression (PMID:35922063), promotes NF-κB activation through IL-1α secretion downstream of TGF-β/Smad signaling (PMID:34679187), drives female-biased autoimmune gene networks and lupus-like disease when overexpressed in skin (PMID:27992404, PMID:30996136), and promotes cardiac and keloid fibrosis through mechanosensitive nuclear translocation, liquid–liquid phase separation with NONO/EWSR1 condensates, and suppression of miR-29b (PMID:36754961, PMID:39826675). Independent of its transcriptional role, VGLL3 is recruited to DNA damage sites in a PARylation-dependent manner where it stabilizes CtIP (by blocking KLHL15-mediated ubiquitination) and MDC1 (by promoting USP7–MDC1 interaction while limiting TRIP12–MDC1), enabling RNF8 signaling and homologous recombination (PMID:39383226).

1. 2010 Medium

   Establishing that VGLL3 is a TEAD cofactor relevant to cancer cell proliferation answered the basic question of its molecular identity and showed that its amplification in soft tissue sarcomas has functional consequences.

   Evidence Array-CGH, siRNA knockdown with proliferation/migration assays in sarcoma cell lines

   PMID:20842732

   Open questions at the time

   • No direct TEAD binding demonstrated
   • Mechanism of proliferation/migration control undefined
   • Single cancer type studied
2. 2016 High

   Identifying VGLL3 as a female-biased transcription cofactor driving autoimmune-associated gene networks revealed a sex-dimorphic, hormone-independent mechanism for autoimmune susceptibility.

   Evidence Global transcriptome analysis and genome-wide VGLL3 target gene mapping across autoimmune disease contexts

   PMID:27992404

   Open questions at the time

   • Downstream effector mechanisms not defined
   • Causal role in autoimmune disease not yet demonstrated in vivo
3. 2019 High

   Interaction proteomics defined TEAD1/3/4 as direct VGLL3 partners in myoblasts and showed VGLL3 mainly represses transcription, establishing its role in myogenic differentiation distinct from YAP/TAZ signaling.

   Evidence Co-IP/mass spectrometry, siRNA knockdown, overexpression with gene expression profiling, Vgll3-null mouse in myoblasts/myotubes

   PMID:31138678

   Open questions at the time

   • Structural basis of VGLL3–TEAD interaction not resolved
   • Mechanism of transcriptional repression unknown
4. 2019 High

   In vivo gain-of-function demonstrated that epidermal VGLL3 overexpression is sufficient to drive systemic lupus-like autoimmunity, causally linking VGLL3 to autoimmune disease through BAFF, IFN-κ, and CXCL13 induction.

   Evidence Transgenic mouse with skin-directed VGLL3 overexpression, immunological and histopathological characterization

   PMID:30996136

   Open questions at the time

   • Precise TEAD-dependent versus TEAD-independent contributions unclear
   • Human disease causality not established
5. 2020 Medium

   Defining VGLL3 as an activator of the Hippo negative-feedback loop (via LATS2/AMOTL2 induction and consequent YAP/TAZ inactivation) resolved how VGLL3 and YAP/TAZ exert opposing effects despite sharing TEAD partners.

   Evidence Stable overexpression and knockdown with Western blot for Hippo pathway components and YAP/TAZ nuclear localization assays

   PMID:32385107

   Open questions at the time

   • Context-dependency across cell types not explored
   • Whether VGLL3 directly competes with YAP/TAZ for TEAD binding not tested biochemically
6. 2020 Medium

   Linking VGLL3 to the IFNα–p53–IL-17C stress response axis under energy stress conditions extended its function beyond steady-state transcription to cellular stress sensing.

   Evidence Cell-based assays with IFNα stimulation under energy stress, gene expression and cell death readouts

   PMID:32803756

   Open questions at the time

   • Mechanism of energy-stress-dependent VGLL3 induction not defined
   • Not confirmed in vivo
7. 2021 Medium

   Demonstrating that TGF-β/Smad3/4 induces VGLL3, which then drives IL-1α secretion and NF-κB activation, placed VGLL3 as a signal integrator connecting TGF-β to inflammatory NF-κB signaling.

   Evidence VGLL3-expressing cell lines, NF-κB reporter assays, TGF-β stimulation, Smad knockdown

   PMID:34679187

   Open questions at the time

   • Whether VGLL3 directly regulates IL-1α transcription via TEAD sites not shown
   • In vivo relevance not tested
8. 2022 High

   Unbiased CRISPR screens identified a VGLL3–TEAD1–RUNX1/3 complex driving PD-L1/PD-L2 expression, defining a specific immune checkpoint regulatory mechanism and expanding the repertoire of VGLL3 partner transcription factors beyond TEADs alone.

   Evidence Genome-wide CRISPR activation screen, secondary partner screen, VGLL3 KO with PD-L1/2 readout in keratinocytes

   PMID:35922063

   Open questions at the time

   • In vivo immune evasion consequences not tested
   • Structural basis of TEAD1–RUNX1/3–VGLL3 ternary complex unknown
9. 2022 Medium

   Placing VGLL3 as an inhibitor of WWTR1/TAZ to activate the IRF3–IFN-β1 axis in rheumatoid arthritis synoviocytes clarified how VGLL3 amplifies type I IFN signaling in autoimmune contexts.

   Evidence VGLL3 overexpression in RA-FLS, RNA-seq, siRNA knockdown of WWTR1/AMOTL2

   PMID:35941675

   Open questions at the time

   • Direct VGLL3-TAZ inhibitory mechanism not defined
   • Single disease tissue context
10. 2023 High

    Demonstrating that substrate stiffness drives integrin β1–Rho–actin-dependent VGLL3 nuclear translocation, where VGLL3 undergoes LLPS in NONO/EWSR1 condensates to suppress miR-29b and promote collagen production, revealed a mechanosensitive phase-separation mechanism for fibrosis; Vgll3-KO mice showed reduced cardiac fibrosis after MI.

    Evidence Vgll3-KO mouse MI model, live-cell imaging/FRAP of phase separation, co-IP of VGLL3–EWSR1, integrin β1/Rho/actin pathway perturbation

    PMID:36754961

    Open questions at the time

    • Whether LLPS is required (vs. correlative) for collagen regulation not tested by phase-separation-deficient mutant rescue
    • How VGLL3–EWSR1 condensates suppress miR-29b transcription mechanistically unclear
11. 2023 Medium

    Showing that VGLL3 promotes slow-twitch muscle fiber specification by inducing PGC-1α—and that proteasomal VGLL3 degradation switches TEAD cofactors from VGLL3 to YAP/TAZ—established a dynamic competition model governing muscle fiber-type identity.

    Evidence Stable VGLL3-expressing C2C12 myocytes, proteasome inhibitor experiments, fiber-type marker analysis

    PMID:37262950

    Open questions at the time

    • Ubiquitin ligase responsible for VGLL3 degradation not identified
    • Not validated in primary muscle or in vivo
12. 2024 High

    Discovering PARylation-dependent recruitment of VGLL3 to DNA damage sites, where it stabilizes CtIP (blocking KLHL15-mediated degradation) and MDC1 (promoting USP7 while limiting TRIP12), established a transcription-independent role for VGLL3 in homologous recombination and DNA damage response.

    Evidence siRNA/KO depletion, live-cell imaging of DNA damage recruitment, co-IP of VGLL3 with KLHL15/MDC1/TRIP12/USP7, HR efficiency assays, xenograft model with etoposide

    PMID:39383226

    Open questions at the time

    • Whether TEAD binding and DDR functions are structurally separable not tested with separation-of-function mutants
    • PAR-binding domain in VGLL3 not mapped
13. 2024 Medium

    Genetic epistasis positioned VGLL3 downstream of HERC6–LATS2 signaling, linking IFN-induced ubiquitin ligase activity to VGLL3-driven female-biased immune responses.

    Evidence HERC6 siRNA in keratinocytes, cGAMP stimulation, rescue by VGLL3 depletion

    PMID:38327798

    Open questions at the time

    • Whether HERC6 directly modifies VGLL3 or acts indirectly via LATS2 not distinguished
    • Single cell type
14. 2024 Low

    Comparative structural analysis revealed that VGLL3 lacks a functional Ω-loop in its Tondu/TEAD-binding domain (unlike VGLL2), suggesting a distinct TEAD-binding mode.

    Evidence Computational sequence analysis of >2400 VGLL proteins using available structural data

    PMID:39182750

    Open questions at the time

    • No direct structural or biochemical validation of the proposed binding mode difference
    • Functional consequences of Ω-loop absence not tested experimentally
15. 2025 High

    Identifying VGLL3 as upregulated in preeclamptic placentas and demonstrating that placenta-specific Vgll3 deletion protects against preeclampsia in mice established VGLL3 as a driver of placental immune activation, impaired trophoblast differentiation, and endothelial dysfunction upstream of sFLT1.

    Evidence Human single-cell/spatial transcriptomics, in vitro trophoblast/endothelial assays, placenta-specific Vgll3 KO mouse, ex vivo human placenta inhibition

    PMID:41953989

    Open questions at the time

    • Therapeutic modality for VGLL3 inhibition not defined
    • TEAD dependence of placental VGLL3 function not confirmed
16. 2025 Medium

    Demonstrating that VGLL3 activates Wnt/β-catenin signaling through WNT2 in keloid fibroblasts linked VGLL3 to glycolysis-driven fibrosis and expanded its pro-fibrotic role beyond the miR-29b/collagen axis.

    Evidence VGLL3 OE/KD in keloid fibroblasts, WNT2 siRNA rescue, ECAR/OCR metabolic assays

    PMID:39826675

    Open questions at the time

    • Whether VGLL3 directly activates WNT2 transcription via TEAD binding not shown
    • Relationship between Wnt and miR-29b fibrotic pathways downstream of VGLL3 not explored
17. 2026 High

    ChIP-seq and single-nucleus multi-omics placed VGLL3 as a transcriptional target of TAZ that represses adipogenic enhancers, defining the YAP/TAZ→VGLL3 axis controlling adipocyte fate.

    Evidence ChIP-seq for H3K27ac, single-nucleus multi-omics of mouse adipose, TAZ OE/KO, TEAD-binding mutants, Vgll3 KO validation

    PMID:41533786

    Open questions at the time

    • Direct VGLL3 ChIP at adipogenic enhancers not performed
    • Whether VGLL3 represses these enhancers through TEAD or other cofactors is inferred but not definitively shown

• Key unresolved questions include: the structural basis of VGLL3–TEAD interaction and how it differs from YAP/TAZ–TEAD, whether the transcriptional and DDR functions are mediated by separable domains, the identity of the E3 ligase controlling VGLL3 proteasomal turnover, and whether VGLL3-driven autoimmunity is therapeutically targetable.
• No crystal or cryo-EM structure of VGLL3–TEAD complex
• Separation-of-function mutants distinguishing transcriptional from DDR roles not generated
• E3 ligase for VGLL3 degradation unknown
• No pharmacological VGLL3 inhibitor reported