8.A.61 The Cornichon (CNIH) Family (formerly the Erv14 Family)
The yeast Nha1p Na+, K+/H+ antiporter has a house-keeping role in pH and cation homeostasis, being needed to alleviate excess Na+ or K+ from the cytoplasm under high external concentrations of these cations. Erv14p, a putative cargo receptor for transmembrane proteins, is required for trafficking of Nha1p from the endoplasmic reticulum to the plasma membrane. Sensitivity to high Na+ concentrations of the erv14 mutant relevant to the intracellular mislocalization of Nha1p-GFP, together with lower Na+ efflux, indicated the involvement of this mutual association to accomplish the survival of the yeast cell upon sodium stress (Rosas-Santiago et al. 2015). This observation is supported by the protein-protein interaction between Erv14p and Nha1p detected using two assays. These and other results indicated that even though Erv14p interacts with Nha1p through their TM domains, the C-terminus is important not only for the efficient delivery of Nha1p to the plasma membrane but also for its dimerization to accomplish its role in yeast salt tolerance. Other functions of Erv14 involve regulation of export of the bud site, positioning of the axial growth site selection protein AXL2 and possibly other secretory proteins from the endoplasmic reticulum in COPII-coated vesicles. It seems to be required for the normal axial budding pattern in haploid cells (Powers and Barlowe 1998).
Cornichon proteins are 139 - 180 aas in length and usually have 3 apparent, but possibly 4 TMSs with the N-terminus in the cytoplasm (Nakagawa 2019). Some have an internal duplication, thereby having 8 TMSs in a 1 + 3 + 1 + 3 TMS arrangement. These homologues function as shuttles for the export of cargo proteins from the ER of eukaryotes to the plasma membrane. TMS 1 is not cleaved off. These auxiliary subunits control the building and gating of AMPARs (TC# 1.A.10) in the brain. The cryoEM structure has been determined in complex with an AMPA receptor (Nakagawa 2019). CNIH2 and 3 are specialized for AMPARs (subunits GluA1 - 4) and do not dissociate from them (Schwenk and Fakler 2019). They slow deactivation and desensitization, prolonging the open state, enhancing the influx of Na+ and Ca2+. The other two auxilary subunits of AMPARs are the GSG1L (TC# 8.A.16.5) and the TARPs (TC# 8.A.16.2). GSG1L proteins also have 4 TMSs, but in a different arrangement. The C-terminus of the cargo receptor Erv14p affects COPII vesicle formation and cargo delivery (Lagunas-Gomez et al. 2023). AMPA-receptor regulatory proteins, germ-cell-specific gene 1-like protein, and cornichon homologs, intricately modulate AMPA receptors (Gonzalez and Jayaraman 2024).
References:
Cargo receptor for transmembrane proteins, Endoplasmic reticulum vesicle protein, Erv14, of 138 aas and 3 TMSs (Rosas-Santiago et al. 2015). A conserved acidic motif is necessary for correct targetting of proteins to the plasma membrane (Rosas-Santiago et al. 2017).
Erv14 of Saccharomyces cerevisiae
Cornichon 3, CHIH3, CNIH-3 or gamma8 regulatory protein, of 160 aas and 3 or 4 TMSs. It regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs) and promotes their targeting to the cell membrane and synapses while modulating their gating properties by regulating their rates of activation, deactivation and desensitization (Shi et al. 2010). Structures of an AMPA receptor in complex with its auxiliary subunit, cornichon 3, has been determined (Nakagawa 2019). Inhibition of AMPA receptors (AMPARs, TC# 1.A.10.1.1) containing transmembrane AMPAR regulatory protein gamma-8 (TC# 8.A.61.1.10) with JNJ-55511118 (TC#8.A.179.1.1) shows preclinical efficacy in reducing chronic repetitive alcohol self-administration (Hoffman et al. 2021).
Cornichon 3 of Homo sapiens
Complex protein II (COPII), Erv14, of 138 aas and 3 TMSs. MoErv14 mediates the intracellular transport of cell membrane receptors to govern the appressorial formation and pathogenicity of Magnaporthe oryzae (Qian et al. 2023). Magnaporthe oryzae causes rice blasts. During infection, M. oryzae utilizes several transmembrane receptor proteins that sense cell surface cues to induce highly specialized infectious structures called appressoria. Qian et al. 2023 showed that disrupting the coat protein complex II (COPII) cargo protein MoErv14 severely affected appressorium formation and pathogenicity as the ΔMoerv14 mutant is defective not only in cAMP production but also in the phosphorylation of the mitogen-activated protein kinase (MAPK) MoPmk1. Either externally supplementing cAMP or maintaining MoPmk1 phosphorylation suppressed the observed defects in the ΔMoerv14 strain. MoErv14 regulates the transport of MoPth11, a membrane receptor functioning upstream of G-protein/cAMP signaling, and MoWish and MoSho1 function upstream of the Pmk1-MAPK pathway. Thus, the mechanism by which Erv14 functions in regulating the transport of receptors involved in appressorium formation and virulence of the blast fungus was revealed (Qian et al. 2023).
Erv14 of Magnaporthe oryzae
Cornichon, endoplasmic reticulum protein of 144 aas and 3 TMSs. Involved in transport and secretion of TGFα family proteins (Castro et al. 2007). The gating of AMPARs occurs in milliseconds, precisely controlled by a variety of auxiliary subunits, including cornichon and stargazin, that are expressed differentially in the brain (Hawken et al. 2017).
Cornichon of Homo sapiens
Uncharaterized protein of 184 aas and 4 TMSs.
UP of Trypanosoma cruzi
Uncharacterized protein of 188 aas and 3 - 5 TMSs.
UP of Leishmania braziliensis
Cornichon-like protein of 159 aas and 3 TMSs
Cornichon-like protein of Chlamydomonas reinhardtii (Chlamydomonas smithii)
Cornichon, Chi, of 144 aas and 3 TMSs. Acts on TGFα family proteins in the endoplasmic reticulum, mediating or regulating transport and secretion (Castro et al. 2007). It acts as a cargo receptor necessary for the transportation of gurken (grk) to a transitional endoplasmic reticulum (tER) site and promotes its incorporation into coat protein complex II (COPII) vesicles (Bökel et al. 2006).
Chi of Drosophila melanogaster (Fruit fly)
ER-derived vesicles protein ERV14 (Cornichon) of 135 aas and 3 TMSs. A conserved acidic motif is necessary for correct targetting of proteins to the plasma membrane (Rosas-Santiago et al. 2017).
Cornichon of Zea mays (Maize)
Cornichon family AMPA receptor auxiliary protein 2 of 160 aas and 3 TMSs, CNIH-2 or CNIG2. It regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs), and promotes their targeting to the cell membrane and synapses. It also modulates their gating properties by regulating their rates of activation, deactivation and desensitization (Shi et al. 2010; Kato and Witkin 2018). Surface expression of functional AMPARs is enhanced by CNIH-2 to a greater extent than TARP gamma-2, suggesting that this distinction aids in maturation and membrane expression (Certain et al. 2023).
CNIH-2 of Homo sapiens
Cornichon homolog (CNIH1) protein of 146 aas and 3 TMSs. There are 5 paralogs in A. thaiana. CNIH proteins regulate glutamate-like receptors (GLRs). AtGLRs interact with AtCNIH pairs, yielding specific intracellular localizations. AtCNIHs further trigger AtGLR activity in mammalian cells without a ligand. Thus, a regulatory mechanism underlies Ca2+ homeostasis by sorting and activation of AtGLRs by AtCNIHs (Wudick et al. 2018).
CNIH1 of Arabidopsis thaliana (Mouse-ear cress)