Alternative titles; symbols
HGNC Approved Gene Symbol: CANX
Cytogenetic location: 5q35.3 Genomic coordinates (GRCh38): 5:179,678,656-179,731,641 (from NCBI)
Calnexin is a ubiquitously expressed molecular lectin-like chaperone. Together with calreticulin (CALR; 109091), calnexin promotes folding of glycosylated proteins in the endoplasmic reticulum (ER) (summary by Kraus et al., 2010).
Calnexin is a 90-kilodalton integral membrane protein of the ER. It exhibits high affinity for binding calcium ions, which was the means by which it was first identified. Calcium ions are known to play a central role in the regulation of cellular metabolism, including signal transduction events and the transport of proteins through the ER. Calnexin has been shown to be associated with several cell surface proteins during translocation through the ER and has been isolated as a complex with other ER proteins involved in calcium ion-dependent retention of proteins. Tjoelker et al. (1994) isolated cDNA clones of the human, mouse, and rat calnexins. Comparisons of the sequences demonstrated a high level of conservation of sequence identity, suggesting that calnexin performs important cellular functions.
Schwann cell-derived peripheral myelin protein-22 (PMP22; 601097), when mutated or overexpressed, causes heritable neuropathies with a 'gain-of-function' endoplasmic reticulum (ER) phenotype. PMP22 associates in a specific and transient manner with CANX in wildtype sciatic nerves. In the sciatic nerves of the Trembler (TrJ) mouse carrying the same mutation in the PMP22 gene that causes Charcot-Marie-Tooth disease (CMT) in the human, Dickson et al. (2002) found prolonged association of mutant PMP22 with CANX. In cultured cells expressing the TrJ mutant PMP22, CANX and PMP22 colocalized in large intracellular structures identified at the electron microscopy level as myelin-like figures, with CANX localization in the structures dependent on PMP22 glucosylation. Similar intracellular myelin-like figures were also present in Schwann cells of sciatic nerves from homozygous TrJ mice. Sequestration of CANX in intracellular myelin-like figures may be relevant to the pathogenesis of autosomal dominant CMT-related neuropathies.
Using human cell lines, Mueller et al. (2008) identified several components of a protein complex required for retrotranslocation or dislocation of misfolded proteins from the ER lumen to the cytosol for proteasome-dependent degradation. These included SEL1L (602329), HRD1 (SYVN1; 608046), derlin-2 (DERL2; 610304), the ATPase p97 (VCP; 601023), PDI (P4HB; 176790), BIP (HSPA5; 138120), calnexin, AUP1 (602434), UBXD8 (FAF2), UBC6E (UBE2J1; 616175), and OS9 (609677).
By overexpression and knockout analyses in HEK293T cells, Zhang et al. (2022) showed that CANX and CALR decreased ebolavirus entry by selectively downregulating steady-state ebolavirus GP1,2 (EBOV-GP1,2) protein in a cell type-independent manner. In the process of GP1,2 downregulation, CALR was dependent on CANX and PDIA3 (602046), whereas CANX was independent of CALR and PDIA3. Mechanistically, CANX and CALR targeted GP1,2 to autolysosomes for degradation via the ERAD machinery. A ring finger protein, RNF26 (606130), interacted with EBOV-GP1,2 and was involved in downregulation of EBOV-GP1,2, but RNF26 only supported CALR, and not CANX or PDIA3, to downregulate EBOV-GP1,2 in an E3 ubiquitin ligase activity-independent manner. Instead, CANX coopted RNF185 (620096) to interact with EBOV-GP1,2 and polyubiquitinate it on K673 in its cytoplasmic tail via ubiquitin K27 linkage for degradation.
Schrag et al. (2001) determined the 3-dimensional structure of the luminal domain of calnexin to 2.9-angstrom resolution. The structure revealed an extended 140-angstrom arm inserted into a beta sandwich structure characteristic of legume lectins. The arm is composed of tandem repeats of 2 proline-rich sequence motifs that interact with one another in a head-to-tail fashion. Identification of the ligand-binding site established calnexin as a monovalent lectin, providing insight into the mechanism by which the calnexin family of chaperones interacts with monoglucosylated glycoproteins.
Gray et al. (1993) hybridized a CANX cDNA probe to Southern blots of a panel of 31 EcoRI-digested somatic cell human-mouse hybrid DNAs. The CANX probe segregated concordantly with chromosome 5. In situ hybridization with a tritium-labeled calnexin cDNA probe regionally localized the CANX gene to 5q35. Tjoelker et al. (1994) reported the details of the mapping of the human CANX gene to 5q35 as reported in abstract by Gray et al. (1993).
Denzel et al. (2002) found that Canx-null mice were born at the expected mendelian ratio and appeared normal, but about half died within the first 48 hours after birth. After 8 to 10 days, surviving Canx-null mice were significantly smaller than wildtype littermates. They developed an unstable gait with marked truncal ataxia and abnormal behavioral reflexes, and they eventually stopped moving and feeding. Histopathologic analysis detected decreased numbers of large to medium myelinated fibers within the sciatic nerve, and loss of large fibers correlated with the severity of the phenotype.
Kraus et al. (2010) found that Canx -/- mice were indistinguishable from wildtype mice at birth and had a normal life span and fertility. However, Canx -/- mice grew more slowly than wildtype or Canx +/- littermates, and they showed neurologic abnormalities, including gait disturbance with instability, splaying of the hind limbs, ataxia, tremors, lower limb motor defects, and a rolling walk. Canx -/- brain and spinal cord appeared normal, with normal number and distribution of motoneurons, and sympathetic neurons grew normally in culture. Electron microscopic analysis of spinal cord and sciatic nerve of Canx -/- mice revealed defective formation and compaction of myelin sheaths. In Canx -/- brain, abnormalities were observed in large white matter tracts. Electrophysiologic recordings of isolated Canx -/- neonatal spinal cord showed reduced conduction velocity. Examination of Canx -/- retinas showed increased numbers of nuclei in the outer and inner nuclear layers, disorganized nuclei, and vacuolization in the retinal pigment epithelial layer. Histologic examination of other tissues in Canx -/- mice, including immune tissues, failed to detect gross abnormalities.
Denzel, A., Molinari, M., Trigueros, C., Martin, J. E., Velmurgan, S., Brown, S., Stamp, G., Owen, M. J. Early postnatal death and motor disorders in mice congenitally deficient in calnexin expression. Molec. Cell. Biol. 22: 7398-7404, 2002. [PubMed: 12370287] [Full Text: https://doi.org/10.1128/MCB.22.21.7398-7404.2002]
Dickson, K. M., Bergeron, J. J. M., Shames, I., Colby, J., Nguyen, D. T., Chevet, E., Thomas, D. Y., Snipes, G. J. Association of calnexin with mutant peripheral myelin protein-22 ex vivo: a basis for 'gain-of-function' ER diseases. Proc. Nat. Acad. Sci. 99: 9852-9857, 2002. [PubMed: 12119418] [Full Text: https://doi.org/10.1073/pnas.152621799]
Gray, P. W., Byers, M. G., Eddy, R. L., Shows, T. B. The assignment of the calnexin gene to the q35 region of chromosome 5. (Abstract) Human Genome Mapping Workshop 93, Kobe, Japan 1993. P. 9.
Kraus, A., Groenendyk, J., Bedard, K., Baldwin, T. A., Krause, K.-H., Dubois-Dauphin, M., Dyck, J., Rosenbaum, E. E., Korngut, L., Colley, N. J., Gosgnach, S., Zochodne, D., Todd, K., Agellon, L. B., Michalak, M. Calnexin deficiency leads to dysmyelination. J. Biol. Chem. 285: 18928-18938, 2010. [PubMed: 20400506] [Full Text: https://doi.org/10.1074/jbc.M110.107201]
Mueller, B., Klemm, E. J., Spooner, E., Claessen, J. H., Ploegh, H. L. SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins. Proc. Nat. Acad. Sci. 105: 12325-12330, 2008. [PubMed: 18711132] [Full Text: https://doi.org/10.1073/pnas.0805371105]
Schrag, J. D., Bergeron, J. J. M., Li, Y., Borisova, S., Hahn, M., Thomas, D. Y., Cygler, M. The structure of calnexin, an ER chaperone involved in quality control of protein folding. Molec. Cell 8: 633-644, 2001. [PubMed: 11583625] [Full Text: https://doi.org/10.1016/s1097-2765(01)00318-5]
Tjoelker, L. W., Seyfried, C. E., Eddy, R. L., Jr., Byers, M. G., Shows, T. B., Calderon, J., Schreiber, R. B., Gray, P. W. Human, mouse, and rat calnexin cDNA cloning: identification of potential calcium binding motifs and gene localization to human chromosome 5. Biochemistry 33: 3229-3236, 1994. [PubMed: 8136357] [Full Text: https://doi.org/10.1021/bi00177a013]
Zhang, J., Wang, B., Gao, X., Peng, C., Shan, C., Johnson, S. F., Schwartz, R. C., Zheng, Y. H. RNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy. Nature Commun. 13: 6007, 2022. [PubMed: 36224200] [Full Text: https://doi.org/10.1038/s41467-022-33805-9]