Alternative titles; symbols
HGNC Approved Gene Symbol: CASP6
Cytogenetic location: 4q25 Genomic coordinates (GRCh38): 4:109,664,388-109,709,767 (from NCBI)
Fernandes-Alnemri et al. (1995) isolated MCH2, a member of the ced-3 subfamily of apoptotic proteases, by performing PCR on human Jurkat T lymphocytes using degenerate oligonucleotides corresponding to conserved peptides in known apoptotic cysteine proteases. The gene, also symbolized CASP6, encodes a 34-kD protein that is highly homologous to human CPP32 (CASP3; 600636), C. elegans ced-3, mammalian Ich1/Nedd2 (600639), and mammalian interleukin-1-beta converting enzyme (147678). Fernandes-Alnemri et al. (1995) observed 1.7-kb (alpha) and 1.4-kb (beta) transcripts expressed in Jurkat lymphocytes and other cell lines. The authors suggested that these transcripts are alternate splicing variants and found that the alpha, but not the beta, MCH2 protein has protease activity. They also found that MCH2-alpha protein can cleave poly(ADP-ribose) polymerase (173870) in vitro and that its overexpression induces apoptosis in insect Sf9 cells, suggesting that MCH2 is a mediator of apoptosis in mammalian cells.
Using protease assays and immunoblotting experiments, Orth et al. (1996) showed that MCH2, like CPP32 and MCH3, functions downstream of the mammalian cell death inhibitors Bcl2 (151430) and BclXL and of the viral serpin CrmA. Further, they found that granzyme B can functionally activate MCH2, supporting the idea that granzyme B kills cells by activating downstream components of the CED-3/ICE apoptotic pathway. Orth et al. (1996) also showed that MCH2, unlike CPP32 and MCH3, can cleave lamin A to its signature apoptotic fragment.
Zhao et al. (2020) found that liver-specific AMPK (see 602739) knockout aggravated liver damage in mouse nonalcoholic steatohepatitis (NASH) models. AMPK phosphorylated proapoptotic caspase-6 protein to inhibit its activation, keeping hepatocyte apoptosis in check. Suppression of AMPK activity relieved this inhibition, rendering caspase-6 activated in human and mouse NASH. AMPK activation or caspase-6 inhibition, even after the onset of NASH, improved liver damage and fibrosis. Once phosphorylation was decreased, caspase-6 was activated by caspase-3 (600636) or caspase-7 (601761). Active caspase-6 cleaved Bid (601997) to induce cytochrome c release, generating a feed-forward loop that led to hepatocyte death. Thus, Zhao et al. (2020) concluded that the AMPK-caspase-6 axis regulates liver damage in NASH.
Tiso et al. (1996) used radiation hybrid mapping to localize the CASP6 gene to human chromosome 4q25-q26. They observed that 4 CASP family genes each colocalize with autosomal dominant malformative diseases. They suggested that Rieger syndrome (180500) is a candidate genetic disease at the 4q25-q26 locus.
Using fluorescence in situ hybridization, Nasir et al. (1997) mapped the MCH2 gene to 4q24-q25. Verhaegh et al. (1995) demonstrated that a gene in the 4q25-q34 chromosomal segment can complement the ability of a Chinese hamster mutant cell line to inhibit DNA synthesis after gamma- and UV-irradiation. Nasir et al. (1997) suggested that the MCH2 gene may be responsible for this complementary activity.
Uribe et al. (2012) found that Casp6 -/- mice were viable, bred normally, and were born in appropriate mendelian ratios. However, Casp6 -/- mice were hypoactive and displayed learning deficits compared with wildtype mice. Casp6 -/- brains showed normal brain architecture at 3 months of age, but increased cortical and striatal volume at 8 months of age, with elevated striatal neuronal number, and abnormal growth of axons through the corpus callosum. In culture, Casp6 -/- neurons were resilient to nerve growth factor (162030) deprivation and excitotoxic insult. Uribe et al. (2012) concluded that CASP6 has a role in neuronal degeneration and in normal axon pruning during development.
The article by Nikolaev et al. (2009) regarding CASP6, APP (104760), and DR6 (605732) has been retracted.
Fernandes-Alnemri, T., Litwack, G., Alnemri, E. S. Mch2, a new member of the apoptotic Ced-3/Ice cysteine protease gene family. Cancer Res. 55: 2737-2742, 1995. [PubMed: 7796396]
Nasir, J., Theilmann, J. L., Chopra, V., Jones, A. M., Walker, D., Rasper, D. M., Vaillancourt, J. P., Hewitt, J. E., Nicholson, D. W., Hayden, M. R. Localization of the cell death genes CPP32 and Mch-2 to human chromosome 4q. Mammalian Genome 8: 56-59, 1997. [PubMed: 9021152] [Full Text: https://doi.org/10.1007/s003359900349]
Nikolaev, A., McLaughlin, T., O'Leary, D. D. M., Tessier-Lavigne, M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457: 981-989, 2009. Note: Retraction: Nature 625: 204 only, 2024. [PubMed: 19225519] [Full Text: https://doi.org/10.1038/nature07767]
Orth, K., Chinnaiyan, A. M., Garg, M., Froelich, C. J., Dixit, V. M. The CED-3/ICE-like protease Mch2 is activated during apoptosis and cleaves the death substrate lamin A. J. Biol. Chem. 271: 16443-16446, 1996. [PubMed: 8663580]
Tiso, N., Pallavicini, A., Muraro, T., Zimbello, R., Apolloni, E., Valle, G., Lanfranchi, G., Danieli, G. A. Chromosomal localization of the human genes, CPP32, Mch2, Mch3, and Ich-1, involved in cellular apoptosis. Biochem. Biophys. Res. Commun. 225: 983-989, 1996. [PubMed: 8780721] [Full Text: https://doi.org/10.1006/bbrc.1996.1282]
Uribe, V., Wong, B. K. Y., Graham, R. K., Cusack, C. L., Skotte, N. H., Pouladi, M. A., Xie, Y., Feinberg, K., Ou, Y., Ouyang, Y., Deng, Y., Franciosi, S., Bissada, N., Spreeuw, A., Zhang, W., Ehrnhoefer, D. E., Vaid, K., Miller, F. D., Deshmukh, M., Howland, D., Hayden, M. R. Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice. Hum. Molec. Genet. 21: 1954-1967, 2012. [PubMed: 22262731] [Full Text: https://doi.org/10.1093/hmg/dds005]
Verhaegh, G. W. C. T., Jongmans, W., Jaspers, N. G. J., Natarajan, A. T., Oshimura, M., Lohman, P. H. M., Zdzienicka, M. Z. A gene that regulates DNA replication in response to DNA damage is located on human chromosome 4q. Am. J. Hum. Genet. 57: 1095-1103, 1995. [PubMed: 7485160]
Zhao, P., Sun, X., Chaggan, C., Liao, Z., In Wong, K., He, F., Singh, S., Loomba, R., Karin, M., Witztum, J. L., Saltiel, A. R. An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis. Science 367: 652-660, 2020. [PubMed: 32029622] [Full Text: https://doi.org/10.1126/science.aay0542]