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To overcome the challenges of fever and leukocyte recruitment, invasive <jats:italic>S. suis<\/jats:italic> must deploy multiple stress responses forming a network and utilize proteases to degrade short\u2010lived regulatory and misfolded proteins induced by adverse stresses, thereby adapting and evading host immune responses. In this study, we found that <jats:italic>S. suis<\/jats:italic> encodes multiple ATP\u2010dependent proteases, including single\u2010chain FtsH and double\u2010subunit Clp protease complexes ClpAP, ClpBP, ClpCP, and ClpXP, which were activated as the fever of infected mice in vivo. The expression of genes <jats:italic>ftsH<\/jats:italic>, <jats:italic>clpA\/B\/C<\/jats:italic>, and <jats:italic>clpP<\/jats:italic>, but not <jats:italic>clpX<\/jats:italic>, were significantly upregulated in <jats:italic>S. suis<\/jats:italic> in response to heat stress, while were not changed notably under the treatments with several other stresses, including oxidative, acidic, and cold stimulation. FtsH and ClpP were required for <jats:italic>S. suis<\/jats:italic> survival within host blood under heat stress in vitro and in vivo. Deletion of <jats:italic>ftsH<\/jats:italic> or <jats:italic>clpP<\/jats:italic> attenuated the tolerance of <jats:italic>S. suis<\/jats:italic> to heat, oxidative and acidic stresses, and significantly impaired the bacterial survival within macrophages. Further analysis identified that repressor CtsR directly binds and controls the <jats:italic>clpA\/B\/C<\/jats:italic> and <jats:italic>clpP<\/jats:italic> operons and is relieved by heat stress. In summary, the deployments of multiple ATP\u2010dependent proteases form a flexible heat stress response network that appears to allow <jats:italic>S. suis<\/jats:italic> to fine\u2010tune the degradation or refolding of the misfolded proteins to maintain cellular homeostasis and optimal survival during infection.<\/jats:p>","DOI":"10.1002\/jobm.202400030","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T07:25:51Z","timestamp":1718954751000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<i>Streptococcus suis<\/i> Deploys Multiple ATP\u2010Dependent Proteases for Heat Stress Adaptation"],"prefix":"10.1002","volume":"64","author":[{"given":"Jianan","family":"Liu","sequence":"first","affiliation":[{"name":"MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine Nanjing Agricultural University Nanjing China"},{"name":"Key Lab 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