CNIH1

CNIH1 is a conserved endoplasmic reticulum-resident cornichon-family protein that functions as a COPII cargo receptor, selecting specific membrane-associated cargoes for ER export and onward secretion or surface delivery (PMID:17607000, PMID:27122606). It localizes primarily to the ER and ER exit sites, associates with immature TGFα family precursors, and is required for their transport, processing, and secretion; its expression level tunes cargo retention versus export, and it functionally substitutes for yeast Erv14 (PMID:17607000). Mechanistically, CNIH1 recruits proTGFα to the COPII coat in concert with auxiliary cytosolic factors, a recruitment step that precedes and is distinguishable from packaging into COPII vesicles (PMID:27122606). Beyond TGFα, CNIH1 acts as a selective ER-to-plasma-membrane export factor for the δ-opioid receptor and a subset of class A GPCRs, directly binding these receptors and requiring its COPII-binding site for their anterograde trafficking [PMID:bio_10.1101_2025.10.27.684930], and it can also support surface targeting of the Na+/H+ antiporter NHA2 (PMID:41676957). Although CNIH1 physically binds AMPA receptor subunits through conserved membrane-proximal residues, it lacks the extracellular loop elements present in CNIH-2/3 and therefore does not confer the AMPAR gating modulation characteristic of its paralogs, dissociating receptor binding from functional gating control (PMID:25186755, PMID:22815494).

1. 1999 Medium

   Established the earliest expression context for the mammalian cornichon ortholog, showing it is a maternally deposited oocyte transcript before any molecular function was known.

   Evidence EST identification, Northern blot, in situ hybridization and genetic mapping of mouse Cnih

   PMID:10022955

   Open questions at the time

   • No protein-level function assigned
   • Cargo receptor role not yet identified
   • Relevance of oocyte expression to trafficking function unaddressed
2. 2007 High

   Defined CNIH1 as an ER cargo receptor by showing it associates with immature TGFα precursors and controls their transport and secretion, with cross-species rescue of yeast Erv14.

   Evidence Subcellular fractionation, co-IP, yeast Erv14 complementation, and gain/loss-of-function in mammalian cells with secretion readouts

   PMID:17607000

   Open questions at the time

   • Does not define the COPII-coat interaction biochemically
   • Cargo specificity beyond TGFα family unknown
   • Step at which CNIH1 acts in COPII budding not resolved
3. 2016 High

   Resolved where CNIH1 acts in the export pathway, showing it is required to recruit proTGFα to the COPII coat as a step distinct from vesicle packaging, with auxiliary cytosolic factors.

   Evidence CRISPR/Cas9 knockout in HeLa, cell-free COPII budding assay, and in vitro reconstitution of cargo recruitment

   PMID:27122606

   Open questions at the time

   • Identity of auxiliary cytosolic factor(s) not determined
   • Direct CNIH1-COPII contact residues not mapped here
   • Mechanistic separation of recruitment vs packaging not structurally defined
4. 2014 High

   Determined that CNIH1 binds AMPA receptors but cannot modulate their gating, localizing the gating-modulatory determinants to paralog-specific extracellular loop residues absent in CNIH1.

   Evidence Peptide array screening, mutagenesis, single-particle EM of AMPAR-CNIH complexes, and electrophysiology in heterologous cells

   PMID:25186755

   Open questions at the time

   • Physiological significance of CNIH1-AMPAR binding without gating effect unclear
   • Whether CNIH1 traffics AMPARs in neurons not tested
   • No endogenous neuronal validation
5. 2012 Medium

   Provided the functional negative control distinguishing CNIH1 from its paralogs, confirming it does not slow AMPAR deactivation or desensitization.

   Evidence Heterologous expression in tsA201 cells with whole-cell patch-clamp electrophysiology

   PMID:22815494

   Open questions at the time

   • Negative result in recombinant system only
   • Does not address CNIH1 binding to AMPARs
   • Single lab
6. 2025 Medium

   Broadened CNIH1's cargo repertoire to GPCRs, identifying it as a selective ER-to-PM export factor for the δ-opioid receptor and a subset of class A GPCRs that requires its COPII-binding site.

   Evidence Genome-wide CRISPR screen, synchronized cargo-release assay, co-IP, glycosylation analysis, localization imaging and COPII-binding-site mutagenesis (preprint)

   PMID:bio_10.1101_2025.10.27.684930

   Open questions at the time

   • Preprint, not yet peer-reviewed
   • Determinants of GPCR cargo selectivity not defined
   • In vivo physiological role in opioid signaling untested
7. 2026 Medium

   Extended CNIH1 cargo range to an ion transporter, showing it supports plasma-membrane targeting and function of the Na+/H+ antiporter NHA2.

   Evidence Yeast Erv14-replacement complementation with functional ion transport and PM-targeting assays

   PMID:41676957

   Open questions at the time

   • Demonstrated in yeast surrogate rather than native mammalian cells
   • Direct CNIH1-NHA2 interaction not shown
   • Specificity versus other human cornichons not dissected

• How CNIH1 achieves cargo selectivity across structurally diverse clients (TGFα precursors, class A GPCRs, ion transporters) and what cytosolic cofactors and COPII contacts govern recruitment remain unresolved.
• No unifying cargo recognition determinant identified
• Auxiliary cytosolic factor(s) uncharacterized
• No high-resolution structure of CNIH1-cargo or CNIH1-COPII complex