机构：[1]Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China.深圳市康宁医院深圳医学信息中心[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.深圳市康宁医院深圳市人民医院深圳医学信息中心[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
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.
基金：
The authors thank Xuefei Zhu (Shenzhen University) for assistance
in detecting ubiquitination, Shuiming Li (Shenzhen University)
for support during the mass spectrometry experiments, and
Jessica Tamanini (Shenzhen University and ET Editing) for editing
the manuscript before submission. This work was supported
by the Natural Science Foundation of China (grants 82130066,
91942315, 2022YFC2302900, 31800064, and 82100015), the
Science and Technology Project of Guangdong Province (grants
2023A1515010351, 2020A1515111016, and 2020A1515111009),
Guangdong Provincial Key Laboratory of Regional Immunity and
Diseases (grant 2019B030301009), and Shenzhen Bay Laboratory
Open Project (grant SZBL2020090501010).
第一作者机构：[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.
通讯作者：
通讯机构：[1]Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China.[4]Shenzhen Bay Laboratory, Shenzhen, China.[*1]Shenzhen University Medical School, 1066 Xueyuan Boulevard, Shenzhen, 518060 Guangdong, China.
推荐引用方式(GB/T 7714)：
Dai Youchao,Zhu Chuanzhi,Xiao Wei,et al.Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent ferritinophagy to enhance intracellular growth[J].JOURNAL OF CLINICAL INVESTIGATION.2023,133(8):doi:10.1172/JCI159941.
APA：
Dai Youchao,Zhu Chuanzhi,Xiao Wei,Huang Kaisong,Wang Xin...&Cai Yi.(2023).Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent ferritinophagy to enhance intracellular growth.JOURNAL OF CLINICAL INVESTIGATION,133,(8)
MLA：
Dai Youchao,et al."Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent ferritinophagy to enhance intracellular growth".JOURNAL OF CLINICAL INVESTIGATION 133..8(2023)
医学