Caspase-6 (CASP6)
The protein contains 293 amino acids for an estimated molecular weight of 33310 Da.
Cysteine protease that plays essential roles in programmed cell death, axonal degeneration, development and innate immunity (PubMed:8663580, PubMed:32298652). During apoptosis, localizes in the nucleus and cleaves the nuclear structural protein NUMA1 and lamin A/LMNA thereby inducing nuclear shrinkage and fragmentation (PubMed:17401638, PubMed:8663580, PubMed:9463409). Furthermore, cleaves many transcription factors such as NF-kappa-B and cAMP response element-binding protein/CREBBP (PubMed:10559921, PubMed:14657026). Plays an essential role in axon degeneration during axon pruning which is the remodeling of axons during neurogenesis but not apoptosis (By similarity). Regulates B-cell programs both during early development and after antigen stimulation (By similarity). In addition, promotes the ZBP1-mediated activation of programmed cell death pathways including pyroptosis, apoptosis, and necroptosis (PANoptosis) and plays an essential role in defense against viruses (PubMed:32298652). Mechanistically, interacts with RIPK3 and enhances the interaction between RIPK3 and ZBP1, leading to ZBP1-mediated inflammasome activation and cell death (PubMed:32298652). (updated: Feb. 10, 2021)
Protein identification was indicated in the following studies:
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| dbSNP:rs11574697 | |
| dbSNP:rs5030674 | |
| dbSNP:rs5030593 |
The reference OMIM entry for this protein is 601532
Caspase 6, apoptosis-related cysteine protease; casp6
Apoptotic cysteine protease mch2
CLONING
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.GENE FUNCTION
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. Nikolaev et al. (2009) reported that beta-amyloid precursor protein (APP; 104760) and death receptor-6 (DR6; 605732) activate a widespread caspase-dependent self-destruction program. DR6 is broadly expressed by developing neurons, and is required for normal cell body death and axonal pruning both in vivo and after trophic factor deprivation in vitro. Unlike neuronal cell body apoptosis, which requires CASP3, Nikolaev et al. (2009) showed that axonal degeneration requires CASP6, which is activated in a punctate pattern that parallels the pattern of axonal fragmentation. Nikolaev et al. (2009) suggested that an extracellular fragment of APP, acting via DR6 and CASP6, contributes to Alzheimer disease (104300).MAPPING
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.ANIMAL MODEL
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 ... More on the omim web site
Feb. 16, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.
Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 601532 was added.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).