SEC24B

SEC24B is a cargo-selective subunit of the COPII vesicle coat that concentrates specific transmembrane and soluble secretory proteins at ER exit sites for anterograde transport to the Golgi. Structural studies show that SEC24B, together with its paralog SEC24A, selectively recognizes LxxLE and DxE export signals through surface grooves distinct from those used by SEC24C/D, thereby partitioning the secretory proteome among COPII isoforms (PMID:18843296, PMID:17255961). The best-characterized cargo of SEC24B is the planar cell polarity protein VANGL2, whose selective sorting into COPII vesicles by SEC24B is essential for convergent extension and neural tube closure; loss-of-function mutations in SEC24B cause craniorachischisis in mice and are found in human neural tube defect cases (PMID:19966784, PMID:20215345, PMID:23592378). Beyond PCP signaling, SEC24B mediates ER-to-Golgi trafficking of EGFR, PCSK9, and linearly ubiquitinated STING, participates in autophagosome biogenesis through selective pairing with phosphorylated SEC23B, and regulates ferroptotic susceptibility in microglia (PMID:27872256, PMID:32058034, PMID:40536345, PMID:30596474, PMID:36536241).

1. 1999 Medium

   Identification of SEC24B as one of four mammalian Sec24 paralogs, forming a subclass with SEC24A, established that COPII cargo selection in mammals involves a diversified family of Sec24 proteins rather than a single ortholog.

   Evidence Molecular cloning, Northern blot, and co-localization of tagged SEC24B with SEC13 at ER-Golgi membranes by fluorescence microscopy

   PMID:10329445

   Open questions at the time

   • No functional transport assay performed
   • Cargo specificity of SEC24B unknown
   • Interaction with SEC23 subunits not characterized
2. 2007 High

   Demonstration that SEC24 isoform pairs have distinct cargo signal preferences resolved how di-leucine versus other ER export motifs are partitioned, showing SEC24B contributes preferentially to di-leucine-mediated transport.

   Evidence siRNA knockdown of single and paired SEC24 isoforms with ERGIC-53 transport assays and in vitro signal-binding assays

   PMID:17255961

   Open questions at the time

   • Endogenous cargo specificity beyond ERGIC-53 not defined
   • In vivo significance not tested
3. 2008 High

   Crystal structures of all four human SEC24 isoforms revealed that a conserved surface groove in SEC24A/B accommodates LxxLE and DxE motifs while the IxM groove is occluded, providing a structural explanation for isoform-specific cargo discrimination.

   Evidence X-ray crystallography combined with biochemical binding and functional COPII vesicle packaging assays

   PMID:18843296

   Open questions at the time

   • No structure of SEC24B bound to its physiological cargo VANGL2
   • Additional binding sites for non-canonical cargo signals uncharacterized
4. 2009 High

   Forward genetic screens linked SEC24B to neural tube closure by showing it selectively sorts the PCP protein VANGL2 into COPII vesicles; this was the first demonstration that a specific SEC24 paralog controls a defined developmental signaling pathway.

   Evidence ENU mutagenesis in mice; COPII vesicle budding assays; genetic epistasis between Sec24b and Vangl2(LP) alleles

   PMID:19966784 PMID:20215345

   Open questions at the time

   • Molecular details of the SEC24B–VANGL2 binding interface unknown
   • Whether SEC24B sorts other PCP components not resolved
5. 2013 High

   Human NTD-associated missense mutations in SEC24B were shown to impair VANGL2 interaction and localization, translating the mouse findings to human disease and confirming the physiological requirement for SEC24B–VANGL2 sorting in neural tube closure.

   Evidence Co-immunoprecipitation; VANGL2 localization assays; zebrafish overexpression and rescue

   PMID:23592378

   Open questions at the time

   • Penetrance and genetic modifiers in human NTD cohorts not defined
   • Structural basis for how each mutation disrupts VANGL2 binding unknown
6. 2013 Medium

   Extension of SEC24B cargo repertoire to soluble secretory proteins was established through its role in PCSK9 ER exit, demonstrating that cargo selectivity extends beyond transmembrane proteins.

   Evidence Sec24a knockout mice with epistasis to Apoe/Ldlr; PCSK9 secretion assays; later confirmed by SEC24 isoform-specific knockdowns mapping the requirement to PCSK9's C-terminal domain

   PMID:23580231 PMID:32058034

   Open questions at the time

   • SEC24B contribution inferred partly from overlap with SEC24A rather than direct SEC24B knockout
   • Whether SEC24B recognizes a specific sorting signal on PCSK9 CTD is unknown
7. 2016 Medium

   SEC24B was identified as specifically required for biosynthetic ER-to-plasma membrane transport of EGFR, linking COPII cargo selection to receptor tyrosine kinase homeostasis.

   Evidence siRNA knockdown of individual COPII subunits with EGFR transport readouts; RNF11-dependent transcriptional upregulation

   PMID:27872256

   Open questions at the time

   • Sorting signal on EGFR recognized by SEC24B not mapped
   • Redundancy with SEC24D (also required) not fully dissected
8. 2018 High

   The discovery that ULK1-phosphorylated SEC23B selectively pairs with SEC24A/B to promote autophagy flux placed SEC24B at the intersection of COPII trafficking and autophagosome biogenesis, expanding its role beyond conventional secretory transport.

   Evidence In vitro ULK1 kinase assay; co-immunoprecipitation of phospho-SEC23B with SEC24 isoforms; autophagy flux assays; subcellular fractionation

   PMID:30596474

   Open questions at the time

   • What membrane cargo SEC24A/B packages for autophagosomes is unknown
   • Whether SEC24B has autophagy-specific post-translational modifications not tested
9. 2021 High

   Live-cell and EM imaging resolved that SEC24B functions to concentrate cargo at ER exit sites rather than coating Golgi-bound carriers, refining the model of COPII coat dynamics.

   Evidence CRISPR/Cas12a endogenous tagging; RUSH live-cell imaging; perturbation of SEC24B cargo-binding domain; electron microscopy

   PMID:33852719

   Open questions at the time

   • Whether this ERES-resident behavior applies to all SEC24 isoforms not resolved
   • Mechanism by which SEC24B is released from ERES membranes not defined
10. 2022 Medium

    A CRISPR screen in iPSC-derived microglia identified SEC24B as a regulator of ferroptosis, revealing an unexpected connection between COPII-mediated trafficking and iron-dependent cell death.

    Evidence Genome-wide CRISPR screen in microglia tri-culture; ferroptosis phenotypic assays

    PMID:36536241

    Open questions at the time

    • Mechanism by which SEC24B loss alters ferroptotic susceptibility is entirely unresolved
    • Specific cargo whose mis-sorting drives ferroptosis not identified
    • Not independently replicated
11. 2025 Medium

    Linear ubiquitination of STING by LUBAC was shown to direct its binding to SEC24B for ER-to-Golgi trafficking, establishing SEC24B as a reader of a non-canonical cargo signal (linear ubiquitin) in innate immune signaling.

    Evidence Co-immunoprecipitation of STING with SEC24B; LUBAC/OTULIN overexpression and knockdown; STING trafficking assays

    PMID:40536345

    Open questions at the time

    • Whether SEC24B directly binds linear ubiquitin chains or requires an adaptor not determined
    • Structural basis for ubiquitin-dependent recognition unknown
    • Not independently replicated

• Key unresolved questions include the structural basis of SEC24B–VANGL2 recognition, the full endogenous cargo repertoire of SEC24B versus other paralogs, the mechanism linking SEC24B to ferroptosis, and whether linear ubiquitin constitutes a general COPII sorting signal or is STING-specific.
• No structure of SEC24B bound to any physiological cargo
• Comprehensive cargo profiling (e.g., proximity labeling at ERES) not performed
• SEC24B post-translational regulation (beyond phospho-SEC23B pairing) unexplored