How Pathogens Maintain Proteostasis During Infection.

Molecular chaperones play a critical role in proteostasis by aiding the folding of newly synthesized proteins and the refolding of misfolded proteins. Cells must match the protein synthesis rate to the protein folding capacity to avoid the accumulation of unfolded proteins that can form toxic aggregates. The Hsp70 chaperone DnaK binds to ribosomes and decreases protein synthesis in the bacterial pathogen Salmonella enterica serovar Typhimurium when facing cytoplasmic Mg2+ starvation, an infection-relevant stress that disrupts proteostasis. DnaK decreases protein synthesis independently of J-domain cochaperones and nucleotide exchange factor GrpE even though J-domain cochaperones and GrpE are required for DnaK's canonical role in protein folding and refolding. DnaK's activity contrasts with that exhibited by the bacteria-specific chaperone trigger factor, which associates with ribosomes and carries out cotranslational protein folding in Mg2+-abundant conditions. Under infection-relevant conditions, the master regulator of S. typhimurium virulence and Mg2+ homeostasis PhoP promotes the expression of DnaK, but not of J-domain cochaperones, GrpE, or trigger factor, suggesting that the differential expression of chaperones and cochaperones furthers S. typhimurium pathogenesis. Hsp70 chaperones also associate with ribosomes in eukaryotic cells but instead promote protein synthesis, the opposite effect that DnaK binding to ribosomes has in bacteria. Thus, Hsp70 chaperone activity differs across growth conditions and among organisms.