Proteotoxic Stress Induces a Cell-Cycle Arrest by Stimulating Lon to Degrade the Replication Initiator DnaA

• Published in: Cell Vol. 154; no. 3; pp. 623 - 636
• Main Authors: Jonas, Kristina, Liu, Jing, Chien, Peter, Laub, Michael T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-08-2013
• Subjects: Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Caulobacter crescentus; Caulobacter crescentus - cytology; Caulobacter crescentus - genetics; Caulobacter crescentus - physiology; cell cycle; DNA Replication; DNA, Bacterial - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Escherichia coli - metabolism; genetic engineering; heat; Heat-Shock Proteins - metabolism; Heat-Shock Response; Molecular Chaperones - metabolism; Protease La - metabolism; Protein Folding; proteinases; proteins; Sigma Factor - metabolism; Stress, Physiological
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.06.034

The decision to initiate DNA replication is a critical step in the cell cycle of all organisms. Cells often delay replication in the face of stressful conditions, but the underlying mechanisms remain incompletely defined. Here, we demonstrate in Caulobacter crescentus that proteotoxic stress induces a cell-cycle arrest by triggering the degradation of DnaA, the conserved replication initiator. A depletion of available Hsp70 chaperone, DnaK, either through genetic manipulation or heat shock, induces synthesis of the Lon protease, which can directly degrade DnaA. Unexpectedly, we find that unfolded proteins, which accumulate following a loss of DnaK, also allosterically activate Lon to degrade DnaA, thereby ensuring a cell-cycle arrest. Our work reveals a mechanism for regulating DNA replication under adverse growth conditions. Additionally, our data indicate that unfolded proteins can actively and directly alter substrate recognition by cellular proteases.
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•The chaperone DnaK is required for DNA replication and DnaA stability in Caulobacter•Loss of DnaK causes an upregulation of the protease Lon that can degrade native DnaA•Unfolded proteins that are Lon substrates can directly stimulate Lon to degrade DnaA•Stress-induced protein unfolding results in reduced DnaA levels and a G1 arrest
Misfolded proteins in bacteria allosterically stimulate the protease Lon to recognize and degrade DnaA, causing G1 arrest and defining a cell-cycle checkpoint that inhibits DNA replication under conditions of proteotoxic stress.