2. Academic Validation
  3. Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent ferritinophagy to enhance intracellular growth

Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent ferritinophagy to enhance intracellular growth

  • J Clin Invest. 2023 Apr 17;133(8):e159941. doi: 10.1172/JCI159941.
Youchao Dai 1 2,  Chuanzhi Zhu 3,  Wei Xiao 1 4,  Kaisong Huang 5,  Xin Wang 6,  Chenyan Shi 1,  Dachuan Lin 1,  Huihua Zhang 1 2,  Xiaoqian Liu 7 8,  Bin Peng 9,  Yi Gao 10,  Cui Hua Liu 11,  Baoxue Ge 12,  Stefan He Kaufmann 13 14 15,  Carl G Feng 16,  Xinchun Chen 1 4,  Yi Cai 1
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China.
  • 2 Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.
  • 3 Laboratory of Molecular Biology, Beijing Key Laboratory for Drug Resistance Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
  • 4 Shenzhen Bay Laboratory, Shenzhen, China.
  • 5 Zhuhai Center for Disease Control and Prevention, Zhuhai, China.
  • 6 First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 7 Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, China.
  • 8 Department of Infectious Disease, Shenzhen People's Hospital, Second Clinical Medical College of Jinan University, Shenzhen, China.
  • 9 Guangdong Key Laboratory for Genome Stability & Disease Prevention and Carson International Cancer Center, Marshall Laboratory of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, China.
  • 10 School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, China.
  • 11 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Beijing, China.
  • 12 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 13 Max Planck Institute for Infection Biology, Berlin, Germany.
  • 14 Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • 15 Hagler Institute for Advanced Study, Texas A&M University, College Station, Texas, USA.
  • 16 Immunology and Host Defense Group, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
PMID: 37066876 DOI: 10.1172/JCI159941
Abstract

Ferritin, a key regulator of iron homeostasis in macrophages, has been reported to confer host defenses against Mycobacterium tuberculosis (Mtb) Infection. Nuclear receptor coactivator 4 (NCOA4) was recently identified as a cargo receptor in ferritin degradation. Here, we show that Mtb Infection enhanced NCOA4-mediated ferritin degradation in macrophages, which in turn increased the bioavailability of iron to intracellular Mtb and therefore promoted Bacterial growth. Of clinical relevance, the upregulation of FTH1 in macrophages was associated with tuberculosis (TB) disease progression in humans. Mechanistically, Mtb Infection enhanced NCOA4-mediated ferritin degradation through p38/AKT1- and TRIM21-mediated proteasomal degradation of HERC2, an E3 ligase of NCOA4. Finally, we confirmed that NCOA4 deficiency in myeloid cells expedites the clearance of Mtb Infection in a murine model. Together, our findings revealed a strategy by which Mtb hijacks host ferritin metabolism for its own intracellular survival. Therefore, this represents a potential target for host-directed therapy against tuberculosis.

Keywords

Bacterial infections; Immunology; Infectious disease; Innate immunity.

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