CAPZA1

CAPZA1 is the α1 subunit of the heterodimeric CapZ complex that binds the barbed ends of actin filaments and caps them, thereby restraining actin cytoskeleton remodeling and acting as a brake on cancer cell migration, invasion, and epithelial-mesenchymal transition (PMID:28093067). Its capping activity is switched off by two distinct inputs: direct binding of PIP2 releases CAPZA1 from the F-actin barbed end—an event driven by hypoxia through the HIF-1α/RhoA/ROCK1 axis (PMID:30742939)—and interaction with the CPI domain of FAM21C, which likewise inhibits capping and promotes filament elongation (PMID:35096613); loss of CAPZA1 capping also licenses invadopodia formation marked by cortactin/F-actin co-localization and gelatin degradation (PMID:40796418). CAPZA1 abundance is set by multiple layers of control: it is targeted for proteasomal degradation by the E3 ligase UBR5 (PMID:33777788) and for selective autophagic turnover by the receptor NDP52 acting through its ZF2 domain (PMID:42061478), while its transcription is positively driven by GATA3 (which TGF-β suppresses) (PMID:40796418) and modulated by histone acetylation at its promoter (PMID:31146068). Beyond its cytoskeletal role, nuclear CAPZA1 binds the LRP1 intracellular domain to block LRP1-ICD occupancy of the LAMP1 promoter, suppressing LAMP1 transcription and autolysosome formation and thereby impairing autophagic degradation of the H. pylori oncoprotein CagA, with downstream β-catenin/ESRP1-mediated CD44v9 cancer stem-like cell generation (PMID:30176157, PMID:31146068). CAPZA1 also supports flagellar ultrastructure and redox homeostasis, as its loss disrupts sperm motility, dynein arm organization, and thiol/disulfide balance (PMID:41858859).

1. 2017 Medium

   Established CAPZA1 as a functional actin-capping protein whose level controls cancer cell motility, defining its core cytoskeletal role rather than mere family membership.

   Evidence CAPZA1–actin co-IP plus knockdown/overexpression with migration/invasion assays and orthotopic xenograft in HCC

   PMID:28093067

   Open questions at the time

   • Does not resolve whether the effect requires the CapZ heterodimer (CAPZB partner)
   • No structural detail of barbed-end engagement
2. 2018 Medium

   Revealed an unexpected nuclear, transcription-modulating function for CAPZA1 distinct from cytoskeletal capping, linking it to autophagy control via LAMP1.

   Evidence Nuclear CAPZA1–LRP1-ICD co-IP, ChIP on LAMP1 promoter, and autolysosome formation readout in gastric cells

   PMID:30176157

   Open questions at the time

   • How CAPZA1 partitions between cytoplasm and nucleus is unknown
   • Whether nuclear CAPZA1 retains actin-capping or is a separate pool
3. 2019 Medium

   Identified a direct lipid switch (PIP2) and its upstream hypoxia pathway that uncaps CAPZA1, explaining how the capping brake is released under tumor microenvironment stress.

   Evidence CAPZA1–PIP2 co-IP plus HIF-1α/RhoA/ROCK1 manipulation and invasion assays in HCC

   PMID:30742939

   Open questions at the time

   • PIP2 binding site on CAPZA1 not mapped
   • Quantitative relationship between PIP2 levels and capping kinetics unresolved
4. 2019 Medium

   Connected CAPZA1 accumulation to oncogenic stem-cell programs downstream of impaired CagA autophagy, and showed oxidative stress raises CAPZA1 via promoter histone acetylation.

   Evidence ChIP for H3 acetylation at CAPZA1 promoter, β-catenin/CD44v9 readouts, CAPZA1 overexpression in AGS cells with H. pylori infection

   PMID:31146068

   Open questions at the time

   • Acetyltransferase responsible not identified
   • Causal chain from CAPZA1 to ESRP1 splicing not fully dissected
5. 2021 Medium

   Defined post-translational control of CAPZA1 abundance by the proteasome, showing UBR5 ubiquitinates CAPZA1 to derepress actin dynamics and metastasis.

   Evidence Co-IP/MS identification of UBR5, proteasome inhibitor rescue, and migration/metastasis assays in pancreatic cancer

   PMID:33777788

   Open questions at the time

   • Ubiquitination sites on CAPZA1 not mapped
   • Whether UBR5 acts on monomeric or complexed CAPZA1 unknown
6. 2021 Low

   Provided early evidence that a 3'UTR SNP alters CAPZA1 regulation by miR-875-5p, introducing genotype-dependent expression control.

   Evidence mRNA affinity pull-down and miR-875-5p overexpression with CAPZA1 Western blot

   PMID:33505778

   Open questions at the time

   • Binding confirmed only by pull-down without reciprocal validation
   • Functional consequence of the SNP for tumor behavior not established here
7. 2022 Medium

   Identified FAM21C as a direct protein inhibitor of CAPZA1 capping via its CPI domain, defining a second mechanism for releasing the capping brake.

   Evidence FAM21C–CAPZA1 co-IP, CPI-domain mutagenesis, and F-actin capping/invasion assays in HCC

   PMID:35096613

   Open questions at the time

   • Structural basis of CPI-domain engagement not solved
   • Interplay between FAM21C and PIP2 regulation untested
8. 2025 Medium

   Placed CAPZA1 transcription under GATA3 control and the TGF-β axis, linking signaling to invadopodia-driven invasion through loss of capping.

   Evidence ChIP for GATA3 at CAPZA1 promoter, GATA3 gain/loss, gelatin-degradation invadopodia assay, and TGF-β inhibitor in mice

   PMID:40796418

   Open questions at the time

   • Direct vs indirect GATA3 regulation in different tissues unclear
   • Quantitative contribution of CAPZA1 to invadopodia versus other regulators
9. 2025 Low

   Extended epigenetic control of CAPZA1 to microbial metabolites, showing SCFAs raise CAPZA1 via HDAC inhibition to impair CagA clearance.

   Evidence SCFA treatment with HDAC inhibition, gastric organoid and mouse infection models, patient gastric juice microbiota analysis

   PMID:41586340

   Open questions at the time

   • Direct HDAC–CAPZA1 promoter link not biochemically confirmed
   • Specific HDAC isoform not identified
10. 2026 Medium

    Identified NDP52-mediated selective autophagy as a turnover route for CAPZA1, with consequences for ROS, cell-cycle arrest, and senescence.

    Evidence IP-MS, ZF2-domain deletion mutant, NDP52 KO mice, and CAPZA1 knockdown rescue in nucleus pulposus cells

    PMID:42061478

    Open questions at the time

    • How CAPZA1 is selected for autophagy (ubiquitin or direct) unknown
    • Relationship to UBR5-proteasome pathway not reconciled
11. 2026 Medium

    Showed a coding-region/3'UTR SNP rewires CAPZA1 mRNA stability via competing RNA-binding proteins, explaining genotype-dependent tumor-suppressor activity.

    Evidence Biotin-RNA pulldown/MS, RIP, mRNA decay assays, and allele-specific stable lines with xenografts in ESCC

    PMID:41787560

    Open questions at the time

    • Whether hnRNP K/PTBP1 and UPF1 compete directly is not shown
    • Population frequency/clinical relevance of alleles not addressed
12. 2026 Medium

    Demonstrated a physiological requirement for CAPZA1 in flagellar architecture and redox balance, broadening its role beyond cancer cytoskeletal regulation.

    Evidence CRISPR-Cas9 KO in mouse spermatids and AAV in vivo delivery with TEM, CASA, and thiol/disulfide biochemistry

    PMID:41858859

    Open questions at the time

    • Mechanism linking CAPZA1 to p300/CBP and SLC7A11 not defined
    • Whether the phenotype reflects capping or non-capping functions unresolved

• How CAPZA1's multiple regulatory inputs (PIP2, FAM21C, UBR5, NDP52, SNP-dependent RNA control) are coordinated, and the structural basis of its barbed-end capping and partner interactions, remain unresolved.
• No structural model of CAPZA1 capping or its inhibitor interfaces in the corpus
• Hierarchy among proteasomal, autophagic, transcriptional, and RNA-stability control not integrated
• CAPZB partner relationship in the heterodimer not directly addressed