SEC24D

SEC24D is a cargo-selective component of the COPII coat that mediates ER-to-Golgi transport of specific client proteins, with a particularly critical role in the secretion of extracellular matrix components including procollagen. SEC24D directly recognizes cargo sorting signals—such as the RL motif of SLC6 family neurotransmitter transporters via its DD733–734 residues—and its cargo-binding pocket is essential for procollagen export, as demonstrated by patient mutations causing osteogenesis imperfecta and cranio-lenticulo-sutural dysplasia-like skeletal phenotypes (PMID:17210573, PMID:25683121, PMID:20442775). SEC24D-marked ER exit sites preferentially recruit lipid raft-associated cargo in a TMED2/10-dependent manner, and site-specific O-GlcNAcylation of SEC24D's disordered N-terminus remodels its interactome—including recruitment of myoferlin to facilitate ERES–ERGIC fusion—to accommodate large collagen cargo (PMID:41309618, PMID:40661455). Beyond canonical secretory trafficking, SEC24D is required for autophagosome closure through interactions with CK1δ and ATG9A, and its depletion impairs osteogenic differentiation via ER stress-mediated inactivation of the ATF6/TGF-β/Runx2 axis (PMID:39056365, PMID:40374976).

1. 2007 High

   Establishing that SEC24D is a cargo-selective COPII adaptor resolved whether individual SEC24 paralogs have distinct cargo specificities; SEC24D was shown to directly bind the RL motif of GAT1 through its DD733–734 residues, with this interaction required for ER export of SLC6 family transporters.

   Evidence RNAi, dominant-negative overexpression, site-directed mutagenesis of both cargo and adaptor, co-IP, and ER export assays in mammalian cells

   PMID:17210573

   Open questions at the time

   • Whether DD733–734 recognizes additional non-SLC6 cargo motifs was not tested
   • Structural basis of the RL–DD interaction was not resolved
2. 2010 High

   Forward genetic screens in zebrafish and medaka independently demonstrated that Sec24D is specifically required for ER export of ECM proteins (type II collagen, matrilin) from chondrocytes, while transmembrane proteins like integrins and cadherins exit the ER independently of Sec24D, establishing cargo-class selectivity in vivo.

   Evidence Positional cloning in two vertebrate models, EM showing ER dilation, immunofluorescence for cargo retention, BiP upregulation for ER stress

   PMID:20346938 PMID:20442775

   Open questions at the time

   • Direct biochemical interaction between Sec24D and procollagen cargo signals was not demonstrated
   • Whether ER stress is a secondary consequence or contributes to pathology was unclear
3. 2013 High

   Mouse knockout showed SEC24D is non-redundantly essential before the 8-cell stage, establishing that no other SEC24 paralog compensates for its loss during early mammalian embryogenesis despite overlapping cargo recognition.

   Evidence Targeted gene disruption in mouse with BAC transgene rescue

   PMID:23596517

   Open questions at the time

   • The specific essential cargo at the pre-8-cell stage was not identified
   • Whether lethality reflects a unique cargo or expression-level requirement was unresolved
4. 2015 High

   Patient-derived mutations in SEC24D's cargo-binding pocket and gelsolin-like domain were shown to impair procollagen ER export and cause ER tubule dilation, directly linking SEC24D cargo recognition to human skeletal disease resembling cranio-lenticulo-sutural dysplasia.

   Evidence Whole-exome sequencing of three affected individuals, EM and immunofluorescence of patient fibroblasts

   PMID:25683121

   Open questions at the time

   • Whether SEC24D directly contacts a procollagen sorting signal or acts via a co-receptor was not established
   • Genotype–phenotype correlation across the SEC24D structure was limited
5. 2021 High

   A knock-in experiment replacing Sec24c with Sec24d coding sequence rescued the early lethality of Sec24c-null mice, demonstrating that SEC24C and SEC24D share sufficient molecular function and that their distinct developmental requirements primarily reflect tissue-specific expression patterns rather than cargo-specificity differences.

   Evidence Dual recombinase-mediated cassette exchange generating Sec24c→Sec24d knock-in mice with developmental phenotyping

   PMID:34702932

   Open questions at the time

   • Post-natal and tissue-specific phenotypes of the knock-in were not fully characterized
   • Whether any cargo discriminates between SEC24C and SEC24D in vivo remained unresolved
6. 2024 Medium

   Identifying SEC24D as required for autophagosome closure expanded its function beyond canonical ER-to-Golgi transport; depletion caused accumulation of unsealed isolation membranes, and SEC24D interacted with CK1δ and ATG9A under starvation.

   Evidence siRNA knockdown, autophagosome closure assay, co-immunoprecipitation under starvation conditions

   PMID:39056365

   Open questions at the time

   • Whether SEC24D acts at the autophagosome membrane directly or through ERES-derived vesicles is unknown
   • Reciprocal validation of the CK1δ and ATG9A interactions was not reported
   • The mechanism by which SEC24D promotes membrane sealing was not defined
7. 2025 High

   Multiple 2025 studies collectively defined how SEC24D achieves cargo-class specificity at ER exit sites and how its activity is dynamically regulated: SEC24D-positive ERES preferentially handle lipid raft-associated cargo via TMED2/10, and O-GlcNAcylation of SEC24D's N-terminal disordered region remodels its interactome to recruit myoferlin for ERES–ERGIC fusion during collagen transport; meanwhile, SEC24D loss impairs osteogenesis through ER stress and ATF6/TGF-β/Runx2 axis inactivation.

   Evidence RUSH synchronized trafficking with isoform-specific ERES localization and TMED2/10 dependency (peer-reviewed); crosslinking proteomics and site-specific O-GlcNAc mutagenesis with in vivo zebrafish rescue (preprint); transcriptomics and pathway analysis in MSCs (peer-reviewed)

   PMID:40374976 PMID:40661455 PMID:41309618

   Open questions at the time

   • Structural basis for how O-GlcNAcylation remodels the SEC24D interactome is unknown
   • Whether myoferlin-mediated ERES–ERGIC fusion is specific to collagen-transporting cells or a general mechanism is untested
   • The direct interaction between SEC24D and lipid raft cargo versus indirect recruitment by TMED2/10 is not resolved
8. 2025 Medium

   Identification of a synonymous variant and a 5'UTR variant in SEC24D causing disease through splicing disruption and translational repression, respectively, established that SEC24D protein levels are rate-limiting and subject to post-transcriptional control mechanisms relevant to osteogenesis imperfecta.

   Evidence RNA-seq and Western blot in patient fibroblasts; ASO-mediated rescue of translation from uATG-containing 5'UTR

   PMID:41188448 PMID:41495099

   Open questions at the time

   • Whether ASO rescue of SEC24D levels is sufficient to restore collagen secretion in patient cells was not shown
   • Prevalence of post-transcriptional regulatory variants in SEC24D across OI cohorts is unknown

• Key unresolved questions include the structural basis for how SEC24D directly engages procollagen or its sorting receptor, how O-GlcNAcylation-driven interactome remodeling is spatiotemporally regulated, and whether SEC24D's role in autophagosome closure operates through ERES-derived membrane supply or a distinct mechanism.
• No crystal structure of SEC24D bound to procollagen or a collagen-specific sorting receptor
• Mechanism linking O-GlcNAcylation to specific interactome changes is unresolved
• SEC24D's contribution to autophagosome closure versus canonical COPII transport has not been mechanistically delineated