Alternative titles; symbols
HGNC Approved Gene Symbol: RTN3
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38): 11:63,681,450-63,759,891 (from NCBI)
The reticulons are a group of highly conserved genes with preferential expression in neuroendocrine tissues (see, e.g., RTN1; 600865).
During a subtraction cloning between macula and peripheral retina, Moreira et al. (1999) isolated a novel member of the reticulon gene family, which they designated reticulon-3. The mRNA for RTN3 was approximately 3-fold more abundant in macula than in peripheral retina. The 2,527-bp cDNA encodes a predicted 236-amino acid protein that shows strong sequence similarity with other members of the RTN gene family (see, e.g., 600865). Northern blot analysis showed that RTN3 is widely expressed in human tissues, with highest expression in the brain.
Moreira et al. (1999) determined that the RTN3 gene contains 7 exons and spans more than 15 kb.
By use of somatic cell hybrid and radiation hybrid panels, Moreira et al. (1999) mapped the RTN3 gene to 11q13, between markers D11S4535 and D11S4627. Southern blot analysis identified the presence of at least one pseudogene that was subsequently localized to chromosome 4.
He et al. (2004) found that BACE1 (604252) coimmunoprecipitated with members of the reticulon family of proteins: RTN1, RTN2 (603183), RTN3, and RTN4 (604475). BACE1 colocalized with RTN3 in neurons of human brain gray matter, and with RTN4 in oligodendrocytes in white matter. Overexpression of RTN3 in vitro inhibited BACE1 activity and decreased amyloid precursor protein (APP; 104760) processing. The findings suggested that reticulon proteins are negative modulators of BACE1 activity, and that RTN3 specifically blocks access of BACE1 to APP within neurons.
The integration of endocytic routes is critical to regulate receptor signaling. A nonclathrin endocytic (NCE) pathway of the epidermal growth factor receptor (EGFR; 131550) is activated at high ligand concentrations and targets receptors to degradation, attenuating signaling. Caldieri et al. (2017) performed an unbiased molecular characterization of EGFR-NCE and identified NCE-specific regulators, including the endoplasmic reticulum (ER)-resident protein RTN3 and a specific cargo, CD147 (109480). RTN3 was critical for EGFR/CD147-NCE, promoting the creation of plasma membrane (PM)-ER contact sites that were required for the formation and/or maturation of NCE invaginations. Ca(2+) release at these sites, triggered by inositol 1,4,5-trisphosphate (IP3)-dependent activation of ER Ca(2+) channels, was needed for the completion of EGFR internalization. The authors concluded that they identified a mechanism of EGFR endocytosis that relies on ER-PM contact sites and local Ca(2+) signaling.
Caldieri, G., Barbieri, E., Nappo, G., Raimondi, A., Bonora, M., Conte, A., Verhoef, L. G. G. C., Confalonieri, S., Malabarba, M. G., Bianchi, F., Cuomo, A., Bonaldi, T., Martini, E., Mazza, D., Pinton, P., Tacchetti, C., Polo, S., Di Fiore, P. P., Sigismund, S. Reticulon 3-dependent ER-PM contact sites control EGFR nonclathrin endocytosis. Science 356: 617-624, 2017. [PubMed: 28495747] [Full Text: https://doi.org/10.1126/science.aah6152]
He, W., Lu, Y., Qahwash, I., Hu, X.-Y., Chang, A., Yan, R. Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation. Nature Med. 10: 959-965, 2004. [PubMed: 15286784] [Full Text: https://doi.org/10.1038/nm1088]
Moreira, E. F., Jaworski, C. J., Rodriguez, I. R. Cloning of a novel member of the reticulon gene family (RTN3): gene structure and chromosomal localization to 11q13. Genomics 58: 73-81, 1999. [PubMed: 10331947] [Full Text: https://doi.org/10.1006/geno.1999.5807]