MCA1, also called YCA1, encodes the sole Saccharomyces cerevisiae type I metacaspase. Unlike canonical caspases it is a monomer, because an extra pair of antiparallel beta-strands blocks the dimerization interface. The Q/N-rich N-terminal prodomain targets Mca1 to insoluble protein aggregates, while the C-terminal caspase-like protease domain uses His220 and Cys276 to cleave substrates after basic residues in a calcium-stimulated manner. Mca1 acts in cytosolic protein quality control by limiting insoluble aggregate accumulation during vegetative growth, aging, and proteotoxic stress; raising MCA1 expression reduces aggregate load and extends life span in an Hsp104- and proteasome-dependent manner. It also promotes yeast apoptotic programmed cell death after oxidative stress, chronological aging, and perturbation of mRNA decay.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004197 cysteine-type endopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT metacaspase-family row correctly propagates cysteine-type endopeptidase activity to budding yeast Mca1. Reason: Q08601 belongs to the PTHR48104 metacaspase family and has direct biochemical evidence for a catalytic His220/Cys276 cysteine-protease dyad. The propagated parent activity is broad relative to the experimentally curated calcium-dependent activity rows, but it is still a true inherited Mca1 molecular function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001589523 SUPPORTS TRANSFER The PAINT node propagates the conserved metacaspase clan CD cysteine-protease activity, which budding yeast Mca1 retains. Supporting Evidence: PMID:22761449 Cys 276 and His 220 constitute the catalytic dyad residues |
| GO:0004197 cysteine-type endopeptidase activity | IEA GO_REF:0000117 | ACCEPT | Summary: The automated ARBA cysteine-endopeptidase row is broad but correct. Reason: The ARBA mapping asserts the parent cysteine-endopeptidase activity rather than the more exact calcium-dependent metacaspase activity, but direct structure and mutagenesis of Yca1 show that this parent term is accurate. Supporting Evidence: PMID:22761449 Cys 276 and His 220 constitute the catalytic dyad residues |
| GO:0004198 calcium-dependent cysteine-type endopeptidase activity | IDA PMID:22761449 Crystal structure of the yeast metacaspase Yca1. | ACCEPT | Summary: Recombinant Yca1 is a Ca(2+)-activated metacaspase protease. Reason: Purified yeast Yca1 undergoes Ca(2+)-stimulated autoprocessing and cleaves a Bir1 fragment in a Ca(2+)-dependent in vitro assay, directly supporting the calcium-dependent cysteine endopeptidase activity. Supporting Evidence: PMID:22761449 the proteolytic activity of Yca1 is also markedly stimulated by Ca 2+ |
| GO:0004198 calcium-dependent cysteine-type endopeptidase activity | IDA PMID:29363267 DNA-damage inducible protein 1 is a conserved metacaspase su... | ACCEPT | Summary: Mca1 cleaves Ddi1 under elevated-calcium conditions in yeast. Reason: The cached record is abstract-only, but the abstract directly identifies Ddi1 as a conserved metacaspase substrate in yeast and reports that Ddi1 cleavage occurs when calcium rises in the relevant metabolic setting. Supporting Evidence: PMID:29363267 Ddi1 represents a conserved protein substrate for metacaspases belonging to divergent unicellular eukaryotes PMID:29363267 Ddi1 cleavage is tightly regulated in vivo as it only takes place in yeast when calcium increases but under specific metabolic conditions |
| GO:0004198 calcium-dependent cysteine-type endopeptidase activity | IMP PMID:22761449 Crystal structure of the yeast metacaspase Yca1. | ACCEPT | Summary: The Yca1 His220/Cys276 catalytic dyad is required for Ca(2+)-stimulated protease activity. Reason: Active-site H220A and C276A mutant proteins failed Ca(2+)-stimulated autoprocessing and could not cleave the Bir1 substrate, confirming by perturbation that the Ca(2+)-dependent proteolysis is an intrinsic Mca1 cysteine-protease activity. Supporting Evidence: PMID:22761449 the mutants C276A and H220A failed to undergo Ca 2+ -stimulated autoprocessing PMID:22761449 neither mutant Yca1-C276A nor mutant Yca1-H220A was able to cleave the Bir1p substrate |
| GO:0005634 nucleus | IDA PMID:12062425 A metacaspase of Trypanosoma brucei causes loss of respirati... | ACCEPT | Summary: ScMCA1 GFP reporters were observed in the nucleus. Reason: The cached evidence is abstract-only, but the abstract explicitly states that GFP-tagged ScMCA1 localized to the nucleus. This supports a reporter-localization row without implying that the proteostatic Mca1 pool is exclusively nuclear. Supporting Evidence: PMID:12062425 GFP-fusion reporters of WWM1, ScMCA1 and TbMCA4 localized to the nucleus |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProtKB-SubCell nucleus mapping is consistent with curated nuclear localization of MCA1. Reason: UniProt curates both nucleus and cytoplasm for budding yeast Mca1, and the nucleus mapping agrees with the ScMCA1 GFP reporter evidence. Supporting Evidence: PMID:12062425 GFP-fusion reporters of WWM1, ScMCA1 and TbMCA4 localized to the nucleus |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT cytoplasm activity row is correct for Mca1. Reason: Budding yeast Mca1 is observed diffusely in the cytoplasm at baseline and is recruited to cytosolic protein aggregates after proteotoxic stress, so the propagated cytoplasm is-active-in row is consistent with direct Mca1 localization and aggregate-clearance evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001589523 SUPPORTS TRANSFER The metacaspase PAINT node transfers a conserved cytoplasmic activity site that is directly supported for budding yeast Mca1. Supporting Evidence: PMID:20624963 Yca1-GFP is diffuse throughout the cell and generally excluded from vacuoles in baseline growth conditions |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProtKB-SubCell cytoplasm mapping is supported by Yca1-GFP localization and aggregate recruitment. Reason: UniProt curates Mca1 to the cytoplasm and nucleus, and the cytoplasmic pool is strongly supported by direct Yca1-GFP imaging before and after heat-induced aggregate formation. Supporting Evidence: PMID:20624963 Yca1-GFP is diffuse throughout the cell and generally excluded from vacuoles in baseline growth conditions |
| GO:0005829 cytosol | IDA PMID:24855027 Life-span extension by a metacaspase in the yeast Saccharomy... | ACCEPT | Summary: Mca1 localizes to cytosolic protein quality-control deposits. Reason: The cached paper is abstract-only, but the abstract directly reports Mca1 recruitment to the insoluble protein deposit and juxtanuclear quality-control compartment during aging and proteostatic stress, supporting cytosolic localization. Supporting Evidence: PMID:24855027 Mca1 is recruited to the insoluble protein deposit (IPOD) and juxtanuclear quality-control compartment (JUNQ) during aging and proteostatic stress |
| GO:0006508 proteolysis | IBA GO_REF:0000033 | ACCEPT | Summary: The broad proteolysis row follows from conserved metacaspase activity. Reason: Yca1 has direct evidence for autoprocessing and substrate cleavage, and Ddi1 was later identified as a yeast metacaspase substrate. The term is a broad parent process, but the inherited metacaspase proteolysis assertion is biologically sound for MCA1. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001589523 SUPPORTS TRANSFER The PAINT node transfers the broadly conserved metacaspase proteolysis process. Supporting Evidence: PMID:22761449 the proteolytic activity of Yca1 is also markedly stimulated by Ca 2+ PMID:29363267 Ddi1 represents a conserved protein substrate for metacaspases belonging to divergent unicellular eukaryotes |
| GO:0006515 protein quality control | IMP PMID:20624963 Metacaspase Yca1 is required for clearance of insoluble prot... | ACCEPT | Summary: Mca1 directly limits the accumulation of insoluble protein aggregates. Reason: Deletion and catalytic inactivation of Yca1 caused aggregate and autophagic-body accumulation during log-phase growth, while Yca1-GFP colocalized with Hsp104-marked aggregates and the Q/N-rich prodomain helped deliver Yca1 to insoluble material. This is a core non-death protein-quality-control role. Supporting Evidence: PMID:20624963 Yca1 protein complexes are enriched for aggregate-remodeling chaperones that colocalize with Yca1-GFP fusions PMID:20624963 deletion and inactivation mutants of Yca1 accrue protein aggregates and autophagic bodies during log-phase growth |
| GO:0006915 apoptotic process | IDA PMID:11983181 A caspase-related protease regulates apoptosis in yeast. | ACCEPT | Summary: The founding YCA1 paper supports Mca1 involvement in yeast apoptotic programmed cell death. Reason: Hydrogen peroxide induced apoptotic markers together with a YCA1-dependent caspase-like activity, and the abstract reports both loss of that response after disruption and stimulation after Yor197w/YCA1 overexpression. This is direct evidence for fungal apoptotic programmed cell death, not just a terminal viability readout. Supporting Evidence: PMID:11983181 Hydrogen peroxide treatment induces apoptosis together with a caspase-like enzymatic activity in yeast PMID:11983181 This response is completely abrogated after disruption and strongly stimulated after overexpression of Yor197w |
| GO:0006915 apoptotic process | IMP PMID:16170310 Yeast caspase 1 links messenger RNA stability to apoptosis i... | ACCEPT | Summary: YCA1 deletion suppresses apoptotic phenotypes caused by an mRNA decapping-pathway lesion. Reason: In the Kllsm4Delta1 mRNA-decay mutant, YCA1 deletion reduced rapid death, TUNEL-positive DNA fragmentation, ROS accumulation, and mitochondrial fragmentation while leaving the mRNA-degradation defect intact. This places Mca1 downstream of mRNA-stability stress in the yeast apoptotic death program. Supporting Evidence: PMID:16170310 Deletion of YCA1 in yeast cells mutated in the LSM4 gene prevents mitochondrial fragmentation and rapid cell death during chronological ageing of the culture PMID:16170310 positioning the budding yeast caspase Yca1 as a downstream executor of cell death induced by mRNA stability |
| GO:0006915 apoptotic process | IMP PMID:16301538 Knockout of caspase-like gene, YCA1, abrogates apoptosis and... | ACCEPT | Summary: YCA1 deletion abrogates H2O2-triggered apoptotic markers and increases oxidized-protein accumulation. Reason: The study compared H2O2-treated wild-type and delta yca1 cells and found that YCA1 loss blocked phosphatidylserine externalization and TUNEL-positive nuclei while increasing oxidized protein burden. Those assays connect Mca1 to yeast apoptosis and independently link YCA1 to oxidized-protein quality control. Supporting Evidence: PMID:16301538 apoptosis was abrogated in the Delta yca1 strain, whereas wild type underwent apoptosis as measured by externalization of phosphatidylserine and the display of TUNEL-positive nuclei |
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Download this section (compressed HTML)Q: Which endogenous substrates connect Mca1 Ca(2+)-dependent cleavage to yeast apoptotic programmed cell death, and are they distinct from protein aggregate or proteasome-shuttle substrates such as Ddi1?
Q: Does Mca1 proteolytic activity execute a defined fungal apoptosis step, or does apoptotic suppression by YCA1 deletion partly reflect indirect proteostasis compensation?
Q: How should GO represent metacaspase-dependent fungal programmed cell death relative to metazoan execution-phase apoptosis without importing mammalian intrinsic or extrinsic signaling mechanisms into yeast?
Experiment: Use endogenous MCA1 alleles with catalytic, prodomain-deletion, and substrate-recognition mutations to measure Ddi1 cleavage, aggregate clearance, H2O2-induced phosphatidylserine externalization, TUNEL-positive nuclei, and chronological-aging death in matched strains.
Hypothesis: Mca1 apoptotic death and Mca1 aggregate clearance depend on separable substrates even though both use the same His220/Cys276 protease core.
Type: endogenous separation-of-function yeast genetics
Type I metacaspase; Ca2+-dependent cysteine protease; regulates proteostasis, cleaving specific substrates during the stress response; regulates apoptosis in response to certain triggers; required for clearance of insoluble protein aggregates during normal growth; implicated in cell cycle dynamics and lifespan extension; undergoes autocatalytic processing; similar to mammalian metacaspases, but exists as a monomer due to an extra pair of anti-parallel beta-strands that block dimerization
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