The Lon protease links nucleotide metabolism with proteotoxic stress

Abstract

SummaryDuring stress all cells must maintain proteome quality while sustaining critical processes like DNA replication. In bacteria, the Lon protease is the central route for degradation of misfolded proteins. Here, we show that inCaulobacter crescentusLon controls dNTP pools during stress through degradation of the transcription factor CcrM. We find that elevated dNTP/NTP ratios in Δloncells protects them from deletion of otherwise essential dTTP-producing pathways and shields them from lethality of hydroxyurea, known to catastrophically deplete dNTPs. Increased dNTP production in Δlonresults from higher expression of ribonucleotide reductase driven by increased CcrM. We show that misfolded proteins can stabilize CcrM by competing for limiting protease and Lon-dependent control of dNTPs improves fitness during protein misfolding conditions. We propose that linking dNTP production with the availability of Lon allowsCaulobacterto maintain replication capacity when misfolded protein burden increases, such as during rapid growth or unanticipated proteotoxic stress.HighlightsdCTP deaminase (DCD) is dispensable when Lon protease is absent due to increased dNTP pools.Stabilization of the Lon substrate CcrM transcriptionally upregulates ribonucleotide reductase, affording protection against hydroxyurea.Misfolded proteins can competitively inhibit CcrM degradation by the Lon protease.Titration of protein quality control is a mechanism that allows cells to respond to stresses that lack dedicated signal response pathways.