Tantalizing evidence for caspase‐like protein expression and activity in the cellular stress response of Archaea

Summary An enigmatic feature of microbial evolution is the emergence of programmed cell death (PCD), a genetically controlled form of cell suicide triggered by environmental stimuli. Archaea , the second major prokaryotic domain of life, have been notably absent from the PCD inheritance discussion, due to a lack of genetic homologues. Using the model haloarchaeon Haloferax volcanii , we document extremely high caspase‐specific activity and expression of immunoreactive proteins to human caspase 8 antisera, both of which were induced by salt stress and death and were abolished by in vivo addition of a broad‐spectrum caspase inhibitor. Caspase inhibition severely impaired cell growth under low and high salt stress, demonstrating a critical role in the cellular stress response. In silico analysis of the H. volcanii proteome identified a subset of 18 potential target proteins containing a signature tetrapeptide caspase cleavage motif (IETD), some with putative roles in allosteric regulation, signal transduction, osmotic stress and cell communication. Detection of similarly high activity and expression in other haloarchaea ( Halorubrum and Haloarcula ) and in diverse members of Euryarchaeota (the methanogen Methanosarcina acetivorans and the hyperthermophile Pyrococcus furiosus ) and Crenarchaeota (the acidophile Sulfolobus solfataricus ) argue for a broad representation within the archaeal domain. By playing a role in normal cell function, caspase‐like proteases in Archaea appear to have co‐evolved with other metabolic pathways, broadening their biological roles beyond apoptosis and cell death.