SEC24A

SEC24A is a paralog-specific COPII cargo adaptor that selects discrete cargoes for ER-to-Golgi anterograde transport while also serving a non-canonical role at ER–mitochondria contact sites (PMID:23580231, PMID:33622772). As a cargo adaptor it is required for efficient ER exit of the soluble protein PCSK9, and its loss in mice lowers plasma PCSK9 and raises hepatic LDLR through a receptor-mediated lipoprotein clearance mechanism, with Apoe and Ldlr mutations epistatic to Sec24a loss (PMID:23580231). SEC24A also mediates anterograde trafficking of the transmembrane voltage-gated potassium channel Kv1.3, with which it associates directly, while showing only partial overlap in cargo selectivity with the paralog SEC24B (PMID:23580231, PMID:26156069). Beyond canonical secretion, SEC24A controls the physical colocalization of peripheral tubular ER with mitochondria and the resulting ER-to-mitochondria Ca2+ flux; its loss impairs ER Ca2+ efflux and mitochondrial Ca2+ influx, increases autophagic flux, and reduces apoptosis upon SERCA inhibition, a function not shared by SEC24B, SEC24C, or SEC24D (PMID:33622772). Consistent with this Ca2+-coupled role, SEC24A is an essential mediator of thapsigargin-induced ER stress cell death acting upstream of the UPR, specifically for the SERCA inhibitor and not for tunicamycin or brefeldin A (PMID:30588337). SEC24A is additionally co-opted by hepatitis B virus, forming a specific complex with SEC23B that exports HBV subviral envelope particles via interaction with the envelope S domain through its N-terminal half (PMID:32017353).

1. 2013 High

   Established that SEC24A is not a redundant COPII component but selects specific soluble cargo, defining a physiological pathway from ER export of PCSK9 to lipoprotein receptor regulation.

   Evidence Knockout mouse with epistasis analysis across Apoe/Ldlr mutants, plasma PCSK9 and hepatic LDLR measurements

   PMID:23580231

   Open questions at the time

   • Does not define the cargo-recognition motif on PCSK9 or the binding interface on SEC24A
   • Mechanism of paralog discrimination not resolved
2. 2013 Medium

   Showed that SEC24 paralogs have overlapping but non-identical cargo repertoires, raising the question of how cargo selectivity is partitioned between SEC24A and SEC24B.

   Evidence Genetic comparison of cargo secretion across paralog contexts in the SEC24A-deficient mouse

   PMID:23580231

   Open questions at the time

   • Extent of overlap not quantified across the full cargo set
   • No structural basis for shared versus distinct recognition
3. 2015 Medium

   Extended SEC24A's adaptor role from soluble to transmembrane cargo by demonstrating it is required for export of the Kv1.3 channel and binds it directly.

   Evidence siRNA knockdown ER retention assay plus in vitro binding of recombinant Kv1.3 and SEC24A

   PMID:26156069

   Open questions at the time

   • ER-export signal on Kv1.3 not mapped
   • Single lab, no reciprocal validation of the interaction in vivo
4. 2018 Medium

   Placed SEC24A upstream of the UPR as a selective mediator of cell death triggered by SERCA inhibition, distinguishing it from a general secretory requirement.

   Evidence Genome-wide CRISPR loss-of-function screen with targeted SEC24A knockout validation across multiple ER stressors in HAP1 cells

   PMID:30588337

   Open questions at the time

   • Molecular link between SEC24A and thapsigargin-specific death not defined at this stage
   • Why tunicamycin and brefeldin A responses are spared unexplained
5. 2020 Medium

   Demonstrated a virus-co-opted, paralog-specific SEC24A–SEC23B complex that exports HBV subviral particles, mapping the determinant to the SEC24A N-terminal half.

   Evidence Yeast-based interaction proteomics, paralog-specific siRNA silencing, SVP secretion assay, and N-terminal domain interaction mapping in HBV-expressing liver cells

   PMID:32017353

   Open questions at the time

   • Structural definition of the S-domain/SEC24A interface absent
   • Whether the SEC23B pairing is HBV-specific or a general SEC24A preference unresolved
6. 2021 High

   Revealed a non-canonical SEC24A function at ER–mitochondria contacts, linking ER tubule–mitochondria tethering and Ca2+ transfer to the control of autophagy and apoptosis, and explaining the thapsigargin-specific death phenotype.

   Evidence CRISPR knockout with organelle-specific Ca2+ indicators, ER–mitochondria colocalization imaging, autophagic flux and apoptosis assays, and paralog-specific rescue

   PMID:33622772

   Open questions at the time

   • Whether tethering is direct or requires intermediary contact-site proteins is unknown
   • Relationship between the COPII cargo-adaptor function and the contact-site function not mechanistically reconciled

• How SEC24A reconciles its canonical COPII cargo-selection activity with its membrane-tethering role at ER–mitochondria contacts, and what structural features drive its cargo and paralog specificity, remain unresolved.
• No structural model of SEC24A cargo or partner interfaces in the corpus
• Mechanism of ER–mitochondria tethering not molecularly defined
• Determinants distinguishing SEC24A from other paralogs not established