Alternative titles; symbols
HGNC Approved Gene Symbol: SHISA5
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:48,467,876-48,504,810 (from NCBI)
Zhang et al. (2000) cloned a cDNA encoding Scotin, which they called HSPC217, from CD34 (142230)-positive hematopoietic stem/progenitor cells. The deduced 170-amino acid protein contains an MYB (189990) DNA-binding domain repeat signature. Microarray analysis of 5 hematopoietic cell lines detected low-level expression of Scotin in NB4 and Jurkat cells, but no expression was detected in HL60, K562, and U937 cells.
Bourdon et al. (2002) identified mouse Scotin by differential display of spleen and thymus of normal and p53 (191170)-null mice after gamma irradiation of whole animals. The induced 1.85-kb transcript encodes a deduced 235-amino acid protein. By searching an EST database using the mouse sequence as probe, followed by 5-prime and 3-prime RACE, Bourdon et al. (2002) cloned a full-length cDNA encoding Scotin from a placenta cDNA library. The deduced 240-amino acid human protein shares 70% identity with mouse Scotin. Both the human and the mouse proteins contain an N-terminal signal sequence, a central transmembrane domain composed of 18 hydrophobic amino acids, and a proline/tyrosine domain, and both show an apparent molecular mass of 25 kD by Western blot analysis. Immunolocalization of exogenously expressed Scotin revealed colocalization with endoplasmic reticulum (ER) markers. By mutation analysis, Bourdon et al. (2002) determined that the proline-rich domain is required for ER localization.
By in situ hybridization of developing mouse, Furushima et al. (2007) detected Shisa5 expression in extraembryonic ectoderm at embryonic day 6.5 (E6.5). At E7.75, Shisa5 was expressed in chorion and weakly in yolk sac, and at E8.0, Shisa5 was expressed in foregut and yolk sac. No Shisa5 expression was detected at E9.5. Furushima et al. (2007) noted that there are 2 splice variants of mouse Shisa5.
Pei and Grishin (2012) reported that the deduced 240-amino acid human SHISA5 protein has a domain structure typical of SHISA proteins, including an N-terminal signal peptide, followed by a cysteine-rich domain, a transmembrane domain, and a C-terminal proline-rich region. Several conserved cysteines follow the transmembrane domain of SHISA5 and may be lipid modified. SHISA5 belongs to a SHISA subfamily containing SHISA4 (617326).
Bourdon et al. (2002) noted that mouse thymus and spleen cells underwent massive p53-dependent apoptosis following ultraviolet irradiation or exposure to actinomycin D. They found that Scotin mRNA was induced coincident with apoptosis and was expressed only in spleen and thymus of irradiated wildtype mice and not in the spleen or thymus of irradiated p53 null mice. Using electrophoretic mobility shift assays, they confirmed direct binding between p53 and Scotin, and using a luciferase reporter plasmid driven by the mouse Scotin promoter, they confirmed dose-dependent p53 transactivation. Furthermore, Bourdon et al. (2002) showed that the apoptosis induced by the p53/Scotin pathway is caspase dependent.
Kim et al. (2016) observed upregulation of SCOTIN expression in Huh7 human hepatocellular carcinoma cells treated with the antiviral cytokine IFNB (147640), but not in cells treated with the inflammatory cytokines IL1B (147720) or IL6 (147620). Overexpression of SCOTIN restricted hepatitis C virus (HCV; see 609532) replication and virion production. SCOTIN also promoted autophagosomal degradation of nonstructural protein-5A (NS5A), an ER-localized HCV protein. SCOTIN suppressed HCV replication through autophagy, but it did not directly alter the general autophagy process. SCOTIN bound NS5A via its transmembrane/proline-rich domain, colocalized with LC3 (MAP1LC3A; 601242) in autophagosomes, and was itself degraded through the autophagy process. Kim et al. (2016) concluded that IFNB-induced SCOTIN recruits HCV NS5A to autophagosomes for degradation, thereby restricting HCV replication.
By genomic sequence analysis, Bourdon et al. (2002) determined that the human Scotin gene contains 6 exons. They identified a p53-responsive element of 9 decamers within the mouse Scotin promoter.
By radiation hybrid analysis, Zhang et al. (2000) mapped the human Scotin gene to chromosome 3. By genomic sequence analysis, Bourdon et al. (2002) mapped the Scotin gene to chromosome 3p21.3. They also identified a Scotin pseudogene on chromosome Xq13.1-q13.3.
Bourdon, J.-C., Renzing, J., Robertson, P. L., Fernandes, K. N., Lane, D. P. Scotin, a novel p53-inducible proapoptotic protein located in the ER and the nuclear membrane. J. Cell Biol. 158: 235-246, 2002. [PubMed: 12135983] [Full Text: https://doi.org/10.1083/jcb.200203006]
Furushima, K., Yamamoto, A., Nagano, T., Shibata, M., Miyachi, H., Abe, T., Ohshima, N., Kiyonari, H., Aizawa, S. Mouse homologues of Shisa antagonistic to Wnt and Fgf signalings. Dev. Biol. 306: 480-492, 2007. [PubMed: 17481602] [Full Text: https://doi.org/10.1016/j.ydbio.2007.03.028]
Kim, N., Kim, M.-J., Sung, P. S., Bae, Y. C., Shin, E.-C., Yoo, J.-Y. Interferon-inducible protein SCOTIN interferes with HCV replication through the autolysosomal degradation of NS5A. Nature Commun. 7: 10631, 2016. Note: Electronic Article. [PubMed: 26868272] [Full Text: https://doi.org/10.1038/ncomms10631]
Pei, J., Grishin, N. V. Unexpected diversity in Shisa-like proteins suggests the importance of their roles as transmembrane adaptors. Cell. Signal. 24: 758-769, 2012. [PubMed: 22120523] [Full Text: https://doi.org/10.1016/j.cellsig.2011.11.011]
Zhang, Q.-H., Ye, M., Wu, X.-Y., Ren, S.-X., Zhao, M., Zhao, C.-J., Fu, G., Shen, Y., Fan, H.-Y., Lu, G., Zhong, M., Xu, X.-R., and 9 others. Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells. Genome Res. 10: 1546-1560, 2000. [PubMed: 11042152] [Full Text: https://doi.org/10.1101/gr.140200]