CORO1C

CORO1C is an F-actin-binding protein composed of N-terminal WD repeats forming a β-propeller and a C-terminal coiled-coil domain that mediates oligomerization and membrane association, functioning as a central regulator of Arp2/3-dependent branched actin dynamics at the cell cortex (PMID:12377779, PMID:35657370). It localizes to lamellipodia and membrane ruffles where it interacts with the Arp2/3 complex and cofilin to control actin turnover, protrusion dynamics, and haptotaxis; loss of CORO1C increases branched actin density and impairs cofilin-mediated filament disassembly (PMID:17274980, PMID:35657370). Beyond lamellipodial dynamics, CORO1C functions as a GDP-Rab27a effector coupling stimulus-driven endocytosis of secretory membrane in pancreatic β-cells, directly binds PLS3 in a calcium-dependent manner to rescue endocytosis and axonal defects in SMN-deficient models, and promotes autophagosome formation through a unique second actin-binding site that drives Arp2/3-dependent actin assembly for SQSTM1/p62 body formation and autophagosome structural integrity (PMID:18768935, PMID:27499521, PMID:41968673). CORO1C activity is post-translationally regulated by UBC9-mediated SUMOylation at K19/K311/K440, which enhances Arp2/3 binding, and by PKC-dependent mechanisms that modulate its protein levels (PMID:41912501, PMID:15813925).

1. 2000 Medium

   Initial cloning established CORO1C as a WD-repeat/coiled-coil protein that co-localizes with F-actin, placing it in the coronin family of actin-associated proteins.

   Evidence cDNA isolation, sequence analysis, and immunocytochemical co-localization with F-actin in cultured cells

   PMID:10828594

   Open questions at the time

   • No functional data on actin regulation
   • No binding partners identified
   • Oligomeric state unknown
2. 2002 High

   Biochemical dissection revealed that the C-terminal coiled-coil domain mediates oligomerization (not simple dimerization), F-actin cross-linking, and membrane association, while cytosolic phosphorylation suggested post-translational regulation of localization.

   Evidence Recombinant deletion constructs, in vitro F-actin binding/cross-linking assays, and membrane fractionation

   PMID:12377779

   Open questions at the time

   • Kinase responsible for phosphorylation not identified
   • Oligomer stoichiometry not precisely defined
   • Functional consequence of cross-linking in cells unknown
3. 2005 Medium

   Expression profiling and dominant-negative studies established CORO1C as a neurite outgrowth regulator in the CNS, and PKC-dependent modulation of its protein levels provided the first link to a specific signaling pathway.

   Evidence GFP-tagged truncation constructs in neuro-2a and PC-12 cells, PMA treatment

   PMID:15813925

   Open questions at the time

   • PKC phosphorylation site(s) on CORO1C not mapped
   • Dominant-negative approach does not distinguish direct from indirect effects
   • Mechanism of PKC-dependent protein level reduction unclear
4. 2006 High

   RNAi-based functional analysis and co-immunoprecipitation identified the Arp2/3 complex and cofilin as direct interaction partners, establishing CORO1C as a regulator of branched actin dynamics at lamellipodia with broad cellular roles including wound healing, endocytosis, and cytokinesis.

   Evidence RNAi knockdown with multiple functional cellular assays, Co-IP with Arp2/3 and cofilin

   PMID:17274980

   Open questions at the time

   • Mechanism by which CORO1C coordinates Arp2/3 and cofilin activities not resolved
   • No structural insight into Arp2/3 binding interface
5. 2008 High

   Discovery that CORO1C functions as a GDP-Rab27a effector in pancreatic β-cells revealed an unexpected role outside canonical actin regulation: coupling post-exocytic membrane retrieval to Rab GTPase signaling through the β-propeller domain.

   Evidence Direct binding assays showing GDP-Rab27a specificity, RNAi and dominant-negative inhibition of phogrin internalization and FM4-64 uptake in β-cells

   PMID:18768935 PMID:20362548

   Open questions at the time

   • Whether Rab27a–CORO1C interaction occurs independently of actin binding not tested
   • Structural basis for GDP-specificity unknown
6. 2016 High

   Identification of PLS3 as a direct calcium-dependent binding partner, combined with rescue of endocytosis and axonal defects in SMN-depleted models, connected CORO1C to spinal muscular atrophy-relevant pathways and demonstrated functional synergy between coronin and plastin actin-binding activities.

   Evidence Proteomics-based partner identification, Co-IP, fluid-phase endocytosis assay in SMN-knockdown cells, zebrafish Smn morpholino rescue by CORO1C overexpression

   PMID:27499521

   Open questions at the time

   • Calcium-binding site mediating PLS3 interaction not mapped
   • Whether CORO1C is rate-limiting for endocytosis in SMA patient neurons unknown
7. 2022 High

   Conditional knockout of Coro1B/1C in fibroblasts resolved a long-standing question by showing that coronins function as pro-cofilin factors: their loss increases branched actin density and paradoxically accumulates cofilin at lamellipodia, impairing actin turnover and haptotaxis.

   Evidence Conditional knockout cells, live-cell imaging of protrusion dynamics, Arp2/3 inhibitor epistasis, F-actin quantification

   PMID:35657370

   Open questions at the time

   • Relative contributions of CORO1B versus CORO1C not fully separated
   • Whether coronins directly activate cofilin or indirectly facilitate its access to filaments not determined
8. 2022 Medium

   Domain mapping revealed that CORO1C recruits phospho-PAK4 (pS99) to the leading edge via its C-terminal extension domain (residues 353–457), linking CORO1C to PAK4/RCC2 signaling in directed cell migration.

   Evidence Co-IP with domain deletion and phosphomutant constructs, leading-edge localization imaging, migration assays in gastric cancer cells

   PMID:35593474

   Open questions at the time

   • Direct binding versus scaffold-mediated interaction not distinguished with purified proteins
   • Relevance outside gastric cancer cells not tested
   • RCC2 regulatory mechanism downstream not defined
9. 2026 Medium

   UBC9-mediated SUMOylation at K19, K311, and K440 was identified as a post-translational modification that enhances CORO1C–Arp2/3 binding and promotes cytoskeletal remodeling, providing the first defined mechanism for modulating CORO1C's Arp2/3 interaction strength.

   Evidence IP-mass spectrometry, site-directed mutagenesis of SUMO sites, Co-IP of CORO1C with Arp2/3, UBC9 knockout functional assays

   PMID:41912501

   Open questions at the time

   • Whether SUMOylation affects CORO1C oligomerization or membrane localization not tested
   • In vivo confirmation in non-cancer contexts lacking
   • Interplay between SUMOylation and phosphorylation unknown
10. 2026 High

    A genome-wide screen and knockout mouse model established CORO1C as essential for autophagosome formation through a unique second actin-binding site that drives Arp2/3-dependent branched actin assembly, SQSTM1/p62 body formation, and autophagosome structural integrity, with organismal consequences including starvation sensitivity and cognitive impairment.

    Evidence Haploid ESC loss-of-function screen, coro1c-knockout mice with autophagy flux assays, TEM, behavioral testing, Co-IP with Arp2/3

    PMID:41968673

    Open questions at the time

    • Identity and structural basis of the second actin-binding site not resolved at atomic level
    • Whether autophagy defect underlies cognitive phenotype or is independent not determined
    • Tissue-specific versus systemic contribution to lethality under starvation unclear

• Key unresolved questions include the structural basis for CORO1C's selectivity for GDP-Rab27a over GTP-Rab27a, the precise mechanism by which CORO1C facilitates cofilin-mediated actin disassembly, and how SUMOylation, phosphorylation, and oligomerization are integrated to spatiotemporally control CORO1C activity in different cellular contexts.
• No high-resolution structure of full-length CORO1C or its complexes
• Crosstalk between SUMOylation and PKC phosphorylation unexplored
• Relative physiological importance of autophagy versus migration roles in vivo not separated