{
  "abstract": "Bacterial survival under environmental stress requires precise regulation of protein homeostasis, yet how this is achieved in organisms with streamlined genomes remains incompletely understood. Here, we identify HagF as a previously unrecognized protein that antagonizes the conserved heat-inducible transcriptional repressor HrcA in Chlamydia. Using genetic and biochemical approaches, including overexpression and CRISPRi-mediated knockdown, we show that under non-stressed conditions, HrcA represses hagF along with its five known targets, including hrcA and four chaperone genes. Upon heat stress, HagF is induced and binds HrcA, attenuating its repressor activity. This negative feedback loop enhances chaperone gene induction, particularly from the hrcA-grpE-dnaK operon, and promotes infectious elementary body yield. Notably, HagF is conserved across members of the order Chlamydiales, highlighting a lineage-specific adaptation. Together, these findings define a regulatory circuit in which a specialized antagonist modulates a widely conserved repressor, enabling Chlamydia to couple heat-responsive gene expression with developmental progression and enhance fitness under restrictive conditions. Author summary: Pathogens must adapt to stressful conditions to survive and spread, yet how bacteria with very small genomes accomplish this remains unclear. Chlamydia, a common human pathogen, encounters thermal and other host-associated stresses during infection and must preserve its developmental capacity to remain infectious. In this study, we identify a previously uncharacterized protein, HagF, that helps Chlamydia respond to heat stress. We show that HagF counteracts the activity of HrcA, a conserved protein that normally represses stress-response genes. By inhibiting HrcA, HagF enhances molecular chaperone expression and infectious progeny yield under stress conditions. This interaction forms a feedback loop that fine-tunes gene expression during stress. Our findings reveal how a pathogen with a streamlined genome uses a specialized regulatory protein to control a conserved stress-response system, thereby enabling it to maintain developmental fitness in challenging host environments.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China",
    "Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, United States of America",
    "Department of Parasitology, Central South University Xiangya Medical School, Changsha, Hunan, China",
    "Department of Microbiology and Immunology, University of Texas Health San Antonio, San Antonio, Texas, United States of America"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yehong Huang"
    },
    {
      "affs": [
        1
      ],
      "name": "Yuxuan Wang"
    },
    {
      "affs": [
        2
      ],
      "name": "Matthew Pan"
    },
    {
      "affs": [
        3
      ],
      "name": "Danny Wan"
    },
    {
      "name": "Lingling Wang"
    },
    {
      "name": "Joseph D. Fondell"
    },
    {
      "name": "Xiang Wu"
    },
    {
      "name": "Guangming Zhong"
    },
    {
      "name": "Huizhou Fan"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ahn0dqyk76w72.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.ppat.1014749",
  "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014749",
  "id": "ahn0dqyk76w72",
  "issns": [
    "1553-7374"
  ],
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  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Nucleic acids/DNA/Operons"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/DNA/Operons"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Gene expression"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Genomics"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Genomics/Microbial genomics/Bacterial genomics"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Microbial genetics/Bacterial genetics/Bacterial genomics"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Bacteriology/Bacterial genetics/Bacterial genomics"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Bacterial pathogens/Chlamydia trachomatis"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Microbial genomics/Bacterial genomics"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Bacteria/Chlamydia"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Bacteria/Chlamydia/Chlamydia trachomatis"
    ],
    [
      "plos",
      "/Medicine and health sciences/Medical conditions/Infectious diseases/Sexually transmitted diseases/Chlamydia infection"
    ],
    [
      "plos",
      "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Bacterial pathogens/Chlamydia trachomatis"
    ],
    [
      "plos",
      "/Physical sciences/Physics/Classical mechanics/Mechanical stress/Thermal stresses"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014749&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-04",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/ahn0dqyk76w72.ris",
  "sources": [
    {
      "first_seen": "2026-11-05T12:20:11Z",
      "native_id": "10.1371/journal.ppat.1014749",
      "source": "plos",
      "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014749"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "plos:genetics",
      "subfield": "genetics-genomics"
    },
    {
      "field": "biology",
      "origin": "plos:microbiology",
      "subfield": "microbiology"
    }
  ],
  "title": "A heat-induced HagF-HrcA regulatory loop promotes chlamydial fitness and infectious progeny yield under stress",
  "title_text": "A heat-induced HagF-HrcA regulatory loop promotes chlamydial fitness and infectious progeny yield under stress",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:20:43Z",
  "url": "https://research.draconitic.com/paper/ahn0dqyk76w72",
  "venue": "PLOS Pathogens",
  "versions": []
}