Prokaryotic Caspase Homologs: Phylogenetic Patterns and Functional Characteristics Reveal Considerable Diversity

Abstract

Caspases accomplish initiation and execution of apoptosis, a programmed cell death process specific to metazoans. The existence of prokaryotic caspase homologs, termed metacaspases, has been known for slightly more than a decade. Despite their potential connection to the evolution of programmed cell death in eukaryotes, the phylogenetic distribution and functions of these prokaryotic metacaspase sequences are largely uncharted, while a few experiments imply involvement in programmed cell death. Aiming at providing a more detailed picture of prokaryotic caspase homologs, we applied a computational approach based on Hidden Markov Model search profiles to identify and functionally characterize putative metacaspases in bacterial and archaeal genomes. Out of the total of 1463 analyzed genomes, merely 267 (18%) were identified to contain putative metacaspases, but their taxonomic distribution included most prokaryotic phyla and a few archaea (Euryarchaeota). Metacaspases were particularly abundant in Alphaproteobacteria, Deltaproteobacteria and Cyanobacteria, which harbor many morphologically and developmentally complex organisms, and a distinct correlation was found between abundance and phenotypic complexity in Cyanobacteria. Notably, Bacillus subtilis and Escherichia coli, known to undergo genetically regulated autolysis, lacked metacaspases. Pfam domain architecture analysis combined with operon identification revealed rich and varied configurations among the metacaspase sequences. These imply roles in programmed cell death, but also e.g. in signaling, various enzymatic activities and protein modification. Together our data show a wide and scattered distribution of caspase homologs in prokaryotes with structurally and functionally diverse sub-groups, and with a potentially intriguing evolutionary role. These features will help delineate future characterizations of death pathways in prokaryotes.

The GraS Sensor in Staphylococcus aureus Mediates Resistance to Host Defense Peptides Differing in Mechanisms of Action

“…Likewise, the present data suggest that certain peptides lead to activation of proteases associated with cell death (CDP) which cleave amino acid motifs of caspase-or metacaspase-like substrates. These findings align with responses to HPD actions reflecting pathways (14,15) that are initiated by altered membrane integrity (e.g., permeability [PRM] and potential [ENR]), leading to chromosomal condensation (e.g., SSC [18; this study) and perturbed macromolecular synthesis (19) and yielding rapid and irreversible cell death (see Fig. S2 in the supplemental material).…”

“…The current data suggest that certain HDPs induce cell death pathways in S. aureus such as exist in many other pathogenic bacteria (14,15,(24)(25)(26)(27)(28). For example, when exposed to certain HDPs, S. aureus exhibits a sharp increase in annexin V binding (ANX) consistent with access to hydroxylated or otherwise negatively charged lipids (29).…”

“…Six-parameter multicolor flow cytometry was used to analyze four specific mechanisms of HDP action and two global effects associated with these mechanisms in the parental, ⌬graS, or ⌬EL S. aureus strains: (i) perturbation of cell membrane (CM) energetics (ENR) (e.g., transmembrane potential), (ii) CM permeabilization (PRM), (iii) annexin V binding (ANX) (negatively charged phospholipids and CM turnover (13,14), (iv) caspase-like/metacaspase-like cell death protease induction (CDP) (11,14,15) 6 CFU/ml in PIPES (pH 7.5) or MES (pH 5.5) and exposed to 20 g of each HDP of interest for 1 h at 37°C. Based on extensive pilot data, this peptide concentration was used to achieve approximately 50% survival given the high inoculum of bacteria exposed.…”

BMAA Inhibits Nitrogen Fixation in the Cyanobacterium Nostoc sp. PCC 7120

“…Indeed, PCD has been proposed to cause the demise of phytoplankton blooms including blooms of tropical cyanobacteria [54,55,56,57]. In addition, metacaspases (caspase homologs) are common among bloom-forming cyanobacteria [58]. The involvement of BMAA, alone or in concert with other signaling molecules, in such a cascade is a hypothesis now worth testing experimentally.…”

IAPs on the move: role of inhibitors of apoptosis proteins in cell migration

“…BIR1p is required for proper chromosome segregation and cytokinesis and moreover, YCA1 also has roles in cell cycle regulation, clearance of protein aggregates, and so on. 4, 5, 6 Further, though there are viral IAP homologs, caspase homologs have not been identified in viruses. 1, 2 …”