Life-span extension by a metacaspase in the yeast Saccharomyces cerevisiae

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Science  20 Jun 2014:
Vol. 344, Issue 6190, pp. 1389-1392
DOI: 10.1126/science.1252634

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Yeast metacaspase: Grim Reaper or savior?

Yeast metacaspases are structural and possibly functional homologs of caspases that execute apoptosis—programmed cell death—in higher organisms. Malmgren Hill et al. tested whether yeast metacaspase Mca1 acts as an executioner or beneficial protein during replicative aging of yeast (see the Perspective by Kampinga). Boosting metacaspase levels caused a substantial and robust extension of life span. This lifespan extension was only partly dependent on the caspase activity of Mca1 but required the presence of the protein disaggregase Hsp104. Consistent with a role in proteostasis, Mca1 was recruited to chaperone-enriched aggregates during aging. Mca1 increased aggregate asymmetry during yeast cytokinesis and counteracted the age-associated accumulation of inclusions.

Science, this issue p. 1389; see also p. 1341


Single-cell species harbor ancestral structural homologs of caspase proteases, although the evolutionary benefit of such apoptosis-related proteins in unicellular organisms is unclear. Here, we found that the yeast metacaspase Mca1 is recruited to the insoluble protein deposit (IPOD) and juxtanuclear quality-control compartment (JUNQ) during aging and proteostatic stress. Elevating MCA1 expression counteracted accumulation of unfolded proteins and aggregates and extended life span in a heat shock protein Hsp104 disaggregase– and proteasome-dependent manner. Consistent with a role in protein quality control, genetic interaction analysis revealed that MCA1 buffers against deficiencies in the Hsp40 chaperone YDJ1 in a caspase cysteine–dependent manner. Life-span extension and aggregate management by Mca1 was only partly dependent on its conserved catalytic cysteine, which suggests that Mca1 harbors both caspase-dependent and independent functions related to life-span control.

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