SEC31A

SEC31A is the outer-coat component of the COPII Sec13/31 complex that drives anterograde cargo export from ER exit sites (ERES) and, through regulated assembly of large COPII carriers, supports bulky cargo secretion and autophagosome biogenesis (PMID:24069399, PMID:29604273). Its residence and dynamics at ERES are governed by the Ca2+-binding protein ALG-2, which binds directly to a PXPGF type-2 motif in the proline-rich region (residues 839–851) through a dedicated hydrophobic pocket distinct from the ALIX site, mutually stabilizing the ALG-2/SEC31A pool at ERES and attenuating COPII budding by stabilizing the Sec23/Sec31A interaction (PMID:16957052, PMID:17196169, PMID:20834162, PMID:24069399, PMID:25667979). ALG-2 further bridges SEC31A to Annexin A11, which maintains the stable juxtanuclear ERES pool (PMID:25540196), while the C-terminal helical domain binds p125A/Sec23IP to license outer-coat assembly [PMID:bio_10.1101_2025.05.07.652703]. SEC31A activity is tuned post-translationally: O-GlcNAcylation on Ser964 accelerates vesicle formation by modulating ALG-2 affinity (PMID:29913562), USP8/STAM1-mediated deubiquitination counteracts Cul3 mono-ubiquitination to restrain large-carrier formation and collagen IV secretion (PMID:29604273), and ULK1 phosphorylation under glucose starvation reorganizes COPII to remodel the cell-surface proteome [PMID:bio_10.1101_2025.10.31.685804]. Functionally, SEC31A is required for collagen biosynthesis and secretion, with TGF-β-driven upregulation promoting a collagen-rich, growth-inhibitory microenvironment (PMID:35285061), and is needed for ATG9a-dependent autophagosome formation during osteogenic differentiation (PMID:39361436). Loss of SEC31A causes ER stress and reduced cell viability, and a homozygous nonsense mutation triggering nonsense-mediated decay underlies a human neurological disorder (PMID:30464055). SEC31A N-terminal sequences also form constitutively active oncogenic fusion kinases with ALK and JAK2 (PMID:16161041, PMID:21325169, PMID:20207848).

1. 2006 High

   Established the first regulated protein partner of the COPII outer coat by showing that ALG-2 docks onto SEC31A in a Ca2+-dependent manner, linking ER export to intracellular calcium.

   Evidence Co-IP, GST pulldown, biotin-ALG-2 overlay, RNAi, and Ca2+ chelator/ionophore imaging in cultured cells

   PMID:16957052 PMID:17196169

   Open questions at the time

   • Did not define the binding motif at residue resolution
   • Functional consequence for budding not yet measured
2. 2010 Medium

   Mapped the ALG-2 binding site to residues 839–851 and showed it determines SEC31A retention kinetics, converting the interaction into a defined ERES-residence determinant.

   Evidence Deletion mapping by ALG-2 overlay and FRAP of GFP/RFP fusions in live cells

   PMID:20834162

   Open questions at the time

   • Single-lab FRAP
   • Did not resolve atomic basis of binding
3. 2013 High

   Demonstrated the functional output of ALG-2 binding: Ca2+/ALG-2 attenuates COPII budding while stabilizing the Sec23/Sec31A complex, defining a Ca2+-gated brake on vesicle formation.

   Evidence Reconstituted in vitro COPII budding and liposome recruitment assays with ALG-2 EF-hand mutagenesis

   PMID:24069399

   Open questions at the time

   • In vitro system may not capture cellular regulation
   • Upstream Ca2+ source not defined
4. 2014 Medium

   Identified Annexin A11 as a downstream effector bridged to SEC31A by ALG-2, extending the ERES-stabilization module and linking it to cargo transport kinetics.

   Evidence Co-IP, siRNA, and synchronous transmembrane-cargo transport assay

   PMID:25540196

   Open questions at the time

   • Single lab
   • Mechanism of ERES scattering on AnxA11 loss unresolved
5. 2015 High

   Resolved the structural basis of binding specificity, showing the SEC31A PXPGF motif uses ALG-2 Pocket 3 distinct from the ALIX site, explaining how ALG-2 engages multiple partners independently.

   Evidence X-ray crystallography of the ALG-2–SEC31A peptide complex with pocket-specific mutagenesis

   PMID:25667979

   Open questions at the time

   • Peptide-only structure, not full-length complex
   • Does not address Ca2+ conformational switch in cells
6. 2018 Medium

   Defined post-translational control of SEC31A by O-GlcNAcylation on S964 and by USP8/STAM1 deubiquitination, establishing that vesicle/large-carrier choice is tuned through PTMs and ALG-2 affinity.

   Evidence MS site mapping, S964 mutagenesis, vesicle formation assay; deubiquitination assay with procollagen IV trafficking and collagen secretion readouts

   PMID:29604273 PMID:29913562

   Open questions at the time

   • O-GlcNAc and ubiquitin pathways not integrated
   • Cul3 ubiquitination shown only by inference here
7. 2018 Medium

   Established SEC31A as essential for ER homeostasis and cell survival and causal for human neurological disease via a loss-of-function nonsense mutation.

   Evidence Whole exome sequencing, CRISPR/Cas9 knockout, ER-stress and viability assays, and Drosophila orthologue knockdown

   PMID:30464055

   Open questions at the time

   • Single family/study
   • Cell-type basis of neurological phenotype not defined
8. 2024 Medium

   Connected COPII/SEC31A to autophagy by showing a SEC31A–ATG9a interaction required for autophagosome formation during osteogenic differentiation.

   Evidence Co-IP, siRNA, autophagosome quantification, and in vitro/in vivo osteogenesis assays

   PMID:39361436

   Open questions at the time

   • Single lab
   • Molecular detail of how COPII contributes membrane to autophagosomes unresolved
9. 2025 Medium

   Identified p125A/Sec23IP binding via the SEC31A C-terminal helical domain as essential for outer-coat assembly and collagen tunnel traffic, and ULK1 phosphorylation as a glucose-starvation switch reorganizing COPII to remodel the cell surface.

   Evidence Cell-free reconstitution and domain deletion (preprint); AMPK/ULK1 perturbation with cell-surface proteomics, migration and metastasis assays (preprint)

   PMID:bio_10.1101_2025.05.07.652703 PMID:bio_10.1101_2025.10.31.685804

   Open questions at the time

   • Both findings are preprints not yet peer-reviewed
   • ULK1 phosphosite(s) on SEC31A not pinpointed
10. 2025 Medium

    Showed that tissue-specific regulation of SEC31A function occurs through RBM47-controlled alternative splicing that tunes large lipid-cargo secretion, adding a transcript-level layer to COPII control.

    Evidence Cross-tissue RNA-seq, minigene splicing assay, RBM47 perturbation, and lipid transport assay

    PMID:40436629

    Open questions at the time

    • Single lab
    • Functional protein consequence of the alternative exon not structurally characterized
11. 2025 Low

    Linked SEC31A to insulin signaling and stress survival in pancreatic alpha cells via an insulin receptor interaction, hinting at a tissue-specific signaling role for ER export.

    Evidence Genome-wide CRISPR screen, single Co-IP, and loss-of-function survival assays in alpha cell lines and C. elegans

    PMID:41093834

    Open questions at the time

    • Single Co-IP without reciprocal validation
    • Pathway mechanism connecting ER export to insulin receptor unresolved

• How the multiple regulatory layers (Ca2+/ALG-2, O-GlcNAcylation, ubiquitination/deubiquitination, ULK1 phosphorylation, splicing) are integrated to select between standard COPII vesicles and large carriers for specific cargoes remains unresolved.
• No unified model integrating the PTM and adaptor inputs
• Cargo-selective carrier-size control mechanism undefined