Contribution of the Clp Protease to Bacterial Survival and Mitochondrial Homoeostasis

Abstract

Fast adaptation to environmental changes ensures bacterial survival, and proteolysis represents a key cellular process in adaptation. The Clp protease system is a multi-component machinery responsible for protein homoeostasis, protein quality control, and targeted proteolysis of transcriptional regulators in prokaryotic cells and prokaryote-derived organelles of eukaryotic cells. A functional Clp protease complex consists of the tetradecameric proteolytic core ClpP and a hexameric ATP-consuming Clp-ATPase, several of which can associate with the same proteolytic core. Clp-ATPases confer substrate specificity by recognising specific degradation tags, and further selectivity is conferred by adaptor proteins, together allowing for a fine-tuned degradation process embedded in elaborate regulatory networks. This review focuses on the contribution of the Clp protease system to prokaryotic survival and summarises the current state of knowledge for exemplary bacteria in an increasing degree of interaction with eukaryotic cells. Starting from free-living bacteria as exemplified by a non-pathogenic and a pathogenic member of the Firmicutes, i.e., Bacillus subtilis and Staphylococcus aureus, respectively, we turn our attention to facultative and obligate intracellular bacterial pathogens, i.e., Mycobacterium tuberculosis, Listeria monocytogenes, and Chlamydia trachomatis, and conclude with mitochondria. Under stress conditions, the Clp protease system exerts its pivotal role in the degradation of damaged proteins and controls the timing and extent of the heat-shock response by regulatory proteolysis. Key regulators of developmental programmes like natural competence, motility, and sporulation are also under Clp proteolytic control. In many pathogenic species, the Clp system is required for the expression of virulence factors and essential for colonising the host. In accordance with its evolutionary origin, the human mitochondrial Clp protease strongly resembles its bacterial counterparts, taking a central role in protein quality control and homoeostasis, energy metabolism, and apoptosis in eukaryotic cells, and several cancer cell types depend on it for proliferation.

Keywords: Clp-ATPase; ClpP; Pathogenesis; Regulatory proteolysis; Stress response.