A Temperature-Dependent Switch from Chaperone to Protease in a Widely Conserved Heat Shock Protein

Abstract

Misfolding or unfolding of polypeptides can occur as a consequence of environmental stress and spontaneous mutation. The abundance of general chaperones and proteases suggests that cells distinguish between proteins that can be refolded and "hopeless" cases fated to enter the proteolytic pathway. The mechanisms controlling this key metabolic decision are not well understood. We show here that the widely conserved heat shock protein DegP (HtrA) has both general molecular chaperone and proteolytic activities. The chaperone function dominates at low temperatures, while the proteolytic activity is present at elevated temperatures. These results show that a single cellular factor can switch between two key pathways, controlling protein stability and turnover. Implications of this finding for intracellular protein metabolism are discussed.

The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity

“…15 ± 17 Bacterial HtrA was shown to act as a chaperone below 288C and as an active protease above 378C. 30 In mammalians, HtrA2/Omi is involved in the degradation of aberrantly folded proteins during conditions of cellular stress such as endoplasmatic reticulum stress, heat shock and ischemia-reperfusion, 16,17 but was also proposed to play a role in cell growth regulation. 15 Although originally reported as localized in the endoplasmic reticulum 16 or the nucleus, 17 we detect Omi in isolated mitochondria with an apparent molecular weight of 37 kDa.…”

The homotrimeric structure of HtrA2 is indispensable for executing its serine protease activity

“…HtrA is indispensable for E. coli cell survival by controlling its proteolytic activity to reduce the levels of unfolded or aggregated proteins at elevated temperatures (Lipinska et al, 1990;Skorko-Glonek et al, 1995;Spiess et al, 1999;Krojer et al, 2002).…”

Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response

“…5 More recently, HtrA2 and the putative kinase PINK1 have been proposed to be components of a mitochondrial stress sensing pathway that might be defective in PD patients. 6 HtrA2 may act to protect mitochondria from certain stresses, in a manner similar to the homologous stress-adaptive proteins DegP and DegS in bacteria, 7,8 and may be part of the mechanism underlying the well established but poorly understood link between mitochondrial dysfunction and neurodegenerative disease. 9 Eukaryotic cells respond to diverse stress signals with programmes of nuclear gene expression designed to repair cellular damage or induce apoptosis.…”