SEC31A

SEC31A is the outer-coat subunit of the COPII complex that drives vesicle budding from ER exit sites (ERES), forming a Sec13/31A cage essential for ER-to-Golgi anterograde transport and cell viability (PMID:30464055). Its Pro-rich region (residues 839–851) provides a Ca²⁺-dependent binding site for ALG-2, which—together with annexin A11—stabilizes Sec31A at ERES and modulates budding kinetics; this interaction is structurally mediated through a PXPGF motif engaging ALG-2 Pocket 3 (PMID:16957052, PMID:25667979, PMID:25540196). Sec31A activity is tuned by O-GlcNAcylation at S964 (promoting vesicle formation), Cul3-dependent mono-ubiquitination (promoting large COPII carriers for procollagen), opposing deubiquitination by USP8/STAM1, tissue-specific alternative splicing regulating large-cargo (chylomicron) secretion, and interaction with p125A to couple outer-coat assembly with collagen tunnel traffic (PMID:29913562, PMID:29604273, PMID:40436629). Chromosomal rearrangements generate oncogenic SEC31A–ALK and SEC31A–JAK2 fusion kinases that constitutively activate downstream signaling and drive hematological and solid tumors (PMID:21325169, PMID:20207848).

1. 2006 High

   The question of how Ca²⁺ signaling intersects with COPII coat dynamics was answered by demonstrating that ALG-2 binds Sec31A's Pro-rich region in a Ca²⁺-dependent manner and that the two proteins mutually stabilize each other at ERES.

   Evidence Reciprocal siRNA knockdowns with immunofluorescence colocalization and Ca²⁺ chelator/ionophore treatments in mammalian cells; confirmed by independent GST pull-down and biotin-labeled ALG-2 overlay

   PMID:16957052 PMID:17196169

   Open questions at the time

   • Structural basis of the ALG-2–Sec31A interaction not yet resolved
   • Whether ALG-2 binding promotes or inhibits vesicle budding was unknown
   • No downstream cargo-transport phenotype shown
2. 2006 Medium

   The identification of a SEC31A–ALK fusion gene from a t(2;4) translocation in inflammatory myofibroblastic tumor established that SEC31A's oligomerization domains can drive constitutive kinase activation when fused to a receptor tyrosine kinase.

   Evidence Karyotyping, FISH, 5'-RACE, RT-PCR, and sequence analysis of patient tumor

   PMID:16161041

   Open questions at the time

   • No in vitro kinase reconstitution or transformation assay performed in this study
   • Frequency and clinical spectrum of SEC31A–ALK fusions not established
   • Whether the COPII-coat function of SEC31A is disrupted in fusion-bearing cells was not tested
3. 2010 High

   Mapping the ALG-2 binding site to residues 839–851 and showing via FRAP that this motif controls the high-affinity pool of Sec31A at ERES defined the minimal determinant governing outer-coat residence time.

   Evidence Deletion mutagenesis of the ABS combined with FRAP live-cell imaging and biotin-labeled ALG-2 overlay

   PMID:20834162

   Open questions at the time

   • Structural resolution of the PXPGF motif–ALG-2 interface not yet available
   • Whether modulating Sec31A residence time affects specific cargo classes was untested
4. 2010 Medium

   Demonstration that SEC31A–ALK transforms Ba/F3 cells to growth-factor independence and is sensitive to ALK inhibitors confirmed oncogenic functionality of the fusion and identified targetable downstream effectors (ERK1/2, AKT, STAT3/5).

   Evidence Ba/F3 transformation assay with TAE-684 ALK inhibitor treatment and Western blot of signaling effectors

   PMID:20207848

   Open questions at the time

   • In vivo tumorigenic potential of SEC31A–ALK not demonstrated
   • Only one cell-based model used
5. 2011 High

   The SEC31A–JAK2 fusion was shown to be a constitutively active kinase that transforms cells in vitro and induces T-lymphoblastic lymphoma or myeloid disease in vivo, confirming SEC31A as a recurrent fusion partner in oncogenic kinase translocations.

   Evidence In vitro transformation assay, murine bone marrow transplantation model, JAK inhibitor sensitivity, kinase activity assay

   PMID:21325169

   Open questions at the time

   • Whether SEC31A-driven oligomerization is universally required for kinase activation in all fusion contexts was not tested
   • No patient treatment outcome data
6. 2013 High

   Reconstituted COPII budding assays resolved that ALG-2/Ca²⁺ attenuates vesicle budding by stabilizing the Sec23/Sec31A complex on donor membranes, answering the open question of whether ALG-2 promotes or inhibits budding.

   Evidence In vitro COPII budding reconstitution with liposome recruitment and EF-hand mutagenesis of ALG-2

   PMID:24069399

   Open questions at the time

   • Physiological stimuli that trigger this inhibitory regulation in cells were unidentified
   • Effect on large versus small COPII carriers not distinguished
7. 2014 High

   Discovery that annexin A11 bridges ALG-2 to Sec31A and that its depletion scatters ERES and accelerates transport identified a third component of the Sec31A retention complex and explained spatial organization of ERES.

   Evidence Reciprocal co-immunoprecipitation, siRNA knockdown of AnxA11 and ALG-2, synchronous cargo transport assay

   PMID:25540196

   Open questions at the time

   • How annexin A11's membrane-binding properties contribute to ERES tethering was not addressed
   • Whether this tripartite complex differs across cell types was unknown
8. 2015 High

   Crystal structure of the ALG-2–Sec31A peptide complex revealed that the PXPGF motif binds a novel Pocket 3 distinct from the ALIX-binding Pocket 1, explaining how ALG-2 discriminates between COPII and ESCRT clients.

   Evidence X-ray crystallography with site-directed mutagenesis (Phe85Ala) and competitive binding assays

   PMID:25667979

   Open questions at the time

   • Full-length Sec31A–ALG-2 complex structure unavailable
   • Whether other COPII subunits contact ALG-2 simultaneously was untested
9. 2018 Medium

   Identification of O-GlcNAcylation at S964 and the opposing deubiquitinase USP8/STAM1 axis established that Sec31A is a convergence point for nutrient-sensitive post-translational modifications that tune COPII carrier size and budding rate.

   Evidence Mass spectrometry, site-directed mutagenesis of S964, COPII vesicle formation assay (O-GlcNAc); Co-IP, deubiquitination assay, knockdown/overexpression with collagen secretion readout (USP8)

   PMID:29604273 PMID:29913562

   Open questions at the time

   • Interplay between O-GlcNAcylation and ubiquitination on the same Sec31A molecule not examined
   • Identity of the E3 ligase site for mono-ubiquitination confirmed only as Cul3 in prior literature, not re-mapped here
   • Single-lab findings for each modification
10. 2018 High

    Knockout of SEC31A in human cells and Drosophila demonstrated that the gene is essential for viability, with loss triggering ER stress pathways and cell death, establishing a non-redundant requirement for Sec31A in COPII function.

    Evidence CRISPR/Cas9 knockout in SH-SY5Y and HEK293T cells, qRT-PCR, cell viability assays; Drosophila null mutant analysis showing brain defects and early lethality

    PMID:30464055

    Open questions at the time

    • Whether SEC31B partially compensates in specific tissues was not tested
    • Specific cargo classes most affected by SEC31A loss were not catalogued
11. 2024 Medium

    The finding that SEC31A interacts with ATG9a on autophagosomal seed vesicles and that its depletion impairs autophagosome formation extended Sec31A's role beyond canonical ER-to-Golgi transport to autophagy membrane supply.

    Evidence Co-immunoprecipitation, siRNA knockdown, autophagosome counting, in vivo mouse osteogenesis analysis

    PMID:39361436

    Open questions at the time

    • Whether COPII vesicle identity is maintained during autophagosome membrane donation is unknown
    • Contribution of other COPII subunits to ATG9a interaction not tested
    • Single-lab finding
12. 2025 Medium

    Tissue-specific alternative splicing of a SEC31A exon, regulated by RBM47, was shown to promote large-cargo (chylomicron) transport, revealing a splicing-based mechanism for tuning COPII carrier capacity in digestive tissues.

    Evidence RNA-seq across human tissues, RBM47 knockdown/overexpression, lipid transport assays

    PMID:40436629

    Open questions at the time

    • Which domain of Sec31A the alternative exon encodes and how it alters cage geometry is unknown
    • Functional validation in primary intestinal cells not shown

• Key unresolved questions include the full structural basis of the assembled Sec13/31A cage on native COPII carriers, how the multiple post-translational modifications (O-GlcNAcylation, ubiquitination, phosphorylation) are integrated on individual Sec31A molecules during physiological transitions, and the precise mechanism by which Sec31A contributes membrane to autophagosomes versus canonical secretory vesicles.
• No cryo-EM or cryo-ET structure of mammalian Sec13/31A cage on native membranes
• Combinatorial PTM code on Sec31A not mapped
• Relative contributions of SEC31A versus SEC31B across tissues remain undefined