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Our previous transposon mutagenesis screen identified 95 lung infectivity-associated<jats:named-content content-type=\"genus-species\">F. tularensis<\/jats:named-content>genes, including those encoding the Lon and ClpP proteases. The present study validates the importance of Lon and ClpP in intramacrophage growth and infection of the mammalian host by using unmarked deletion mutants of the<jats:named-content content-type=\"genus-species\">F. tularensis<\/jats:named-content>live vaccine strain (LVS). Further experiments revealed that<jats:italic>lon<\/jats:italic>and<jats:italic>clpP<\/jats:italic>are also required for<jats:named-content content-type=\"genus-species\">F. tularensis<\/jats:named-content>tolerance to stressful conditions. A quantitative proteomic comparison between heat-stressed LVS and the isogenic Lon-deficient mutant identified 29 putative Lon substrate proteins. The follow-up protein degradation experiments identified five substrates of the<jats:named-content content-type=\"genus-species\">F. tularensis<\/jats:named-content>Lon protease (FTL578, FTL663, FTL1217, FTL1228, and FTL1957). FTL578 (ornithine cyclodeaminase), FTL663 (heat shock protein), and FTL1228 (iron-sulfur activator complex subunit SufD) have been previously described as virulence-associated factors in<jats:named-content content-type=\"genus-species\">F. tularensis<\/jats:named-content>. Identification of these Lon substrates has thus provided important clues for further understanding of the<jats:named-content content-type=\"genus-species\">F. tularensis<\/jats:named-content>stress response and pathogenesis. The high-throughput approach developed in this study can be used for systematic identification of the Lon substrates in other prokaryotic and eukaryotic organisms.<\/jats:p>","DOI":"10.1128\/iai.00076-16","type":"journal-article","created":{"date-parts":[[2016,2,23]],"date-time":"2016-02-23T03:43:26Z","timestamp":1456199006000},"page":"1387-1402","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":16,"title":["The Protease Locus of Francisella tularensis LVS Is Required for Stress Tolerance and Infection in the Mammalian Host"],"prefix":"10.1128","volume":"84","author":[{"given":"Lihong","family":"He","sequence":"first","affiliation":[{"name":"Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manoj Kumar Mohan","family":"Nair","sequence":"additional","affiliation":[{"name":"Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuling","family":"Chen","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengyun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karsten R. 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