Unfolded protein responses in bacteria and mitochondria: A central role for the ClpXP machine

Abstract

SummaryIn the crowded environment of a cell, the protein quality control machinery, such as molecular chaperones and proteases, maintains a population of folded and hence functional proteins. The accumulation of unfolded proteins in a cell is particularly harmful as it not only reduces the concentration of active proteins but also overburdens the protein quality control machinery, which in turn, can lead to a significant increase in nonproductive folding and protein aggregation. To circumvent this problem, cells use heat shock and unfolded protein stress response pathways, which essentially sense the change to protein homeostasis upregulating protein quality control factors that act to restore the balance. Interestingly, several stress response pathways are proteolytically controlled. In this review, we provide a brief summary of targeted protein degradation by AAA1 proteases and focus on the role of ClpXP proteases, particularly in the signaling pathway of the Escherichia coli extracellular stress response and the mitochondrial unfolded protein response. IUBMBIUBMB Life, 63(11): 955-963, 2011

Substrate recognition and processing by a Walker B mutant of the human mitochondrial AAA+ protein CLPX

“…In this case, peptides generated from the degradation of unfolded and/or aggregated proteins in response to mitochondrial protein folding stress are proposed to play a critical role in the signaling pathway Kirstein-Miles and Morimoto, 2010), although the target proteins that are degraded by ClpXP remain unknown. Consistent with the idea that ClpXP plays an important role in stress sensing and/or signaling, Escherichia coli ClpXP, through the regulated degradation of key proteins, plays a central role in controlling both, the general and the envelope stress response pathways (for recent reviews see Ades (2008), Battesti et al (2011), Truscott et al (2011). …”

Marching to the beat of the ring: polypeptide translocation by AAA+ proteases

“…Substrate specificity is usually determined through placement of degradation tags, or degrons. Degrons can be intrinsic peptide sequences that are hidden within a correctly folded protein and become exposed only upon protein damage or misfolding, for instance during bacterial heat shock [4]. They can also be appended to a protein during certain checkpoints, for example, in the ssrA-tagging system for stalled protein synthesis.…”

Down-regulation of the mitochondrial matrix peptidase ClpP in muscle cells causes mitochondrial dysfunction and decreases cell proliferation

“…The Lon protease has been studied extensively and has been shown to play an important role in removing oxidized proteins from the mitochondrial matrix [3,4]. ClpP forms complexes with AAA+ chaperone, ClpX to form an active protease ClpXP [5]. Eukaryotic ClpP has been shown to degrade unfolded proteins in the mitochondrial matrix and is induced in response to stress [6–8].…”