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Burkholderia pseudomallei interferes with host lipid metabolism via NR1D2-mediated PNPLA2/ATGL suppression to block autophagy-dependent inhibition of infection.
Autophagy. 2021 08; 17(8):1918-1933.A

Abstract

Burkholderia pseudomallei: which causes melioidosis with high mortality in humans, has become a global public health concern. Recently, infection-driven lipid droplet accumulation has been related to the progression of host-pathogen interactions, and its contribution to the pathogenesis of infectious disease has been investigated. Here, we demonstrated that B. pseudomallei infection actively induced a time-dependent increase in the number and size of lipid droplets in human lung epithelial cells and macrophages. We also found that lipid droplet accumulation following B. pseudomallei infection was associated with downregulation of PNPLA2/ATGL (patatin like phospholipase domain containing 2) and lipophagy inhibition. Functionally, lipid droplet accumulation, facilitated via PNPLA2 downregulation, inhibited macroautophagic/autophagic flux and, thus, hindered autophagy-dependent inhibition of B. pseudomallei infection in lung epithelial cells. Mechanistically, we further revealed that nuclear receptor NR1D2 might be involved in the suppression of PNPLA2 after cell exposure to B. pseudomallei. Taken together, our findings unraveled an evolutionary strategy, by which B. pseudomallei interferes with the host lipid metabolism, to block autophagy-dependent suppression of infection. This study proposes potential targets for clinical therapy of melioidosis.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; ATG7: autophagy related 7; B. pseudomallei: Burkholderia pseudomallei; CFU: colony-forming unit; DG: diglyceride; FASN: fatty acid synthase; GFP: green fluorescent protein; LAMP1: lysosomal associated membrane protein 1; LC-MS/MS: liquid chromatography-tandem mass spectrometry; LD: lipid droplet; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MG: monoglyceride; MOI: multiplicity of infection; mRFP: monomeric red fluorescent protein; NR1D2: nuclear receptor subfamily 1 group D member 2; p.i., post-infection; PLIN2/ADRP: perilipin 2; PNPLA2/ATGL: patatin like phospholipase domain containing 2; Rapa: rapamycin; SQSTM1/p62: sequestosome 1; shRNA: short hairpin RNA; TEM: transmission electron microscopy; TG: triglyceride.

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Tang M
Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing, China. Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Southwest University, Chongqing, China.
Hu Z
Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing, China.
Rao C
Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing, China.
Chen J
Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing, China. Department of General Medicine, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
Yuan S
Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing, China. Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Southwest University, Chongqing, China.
Zhang J
Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
Mao C
Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing, China.
Yan J
Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing, China.
Xia Y
Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing, China.
Zhang M
Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing, China.
Yue J
Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing, China.
Xiang Y
Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing, China.
Xie J
Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Southwest University, Chongqing, China.
Mao X
Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing, China.
Li Q
Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing, China.

MeSH

AutophagyBurkholderia pseudomalleiHumansInfectionsLipaseLipid DropletsLipid MetabolismReceptors, Cytoplasmic and NuclearRepressor Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32777979

Citation

Tang, Mengling, et al. "Burkholderia Pseudomallei Interferes With Host Lipid Metabolism Via NR1D2-mediated PNPLA2/ATGL Suppression to Block Autophagy-dependent Inhibition of Infection." Autophagy, vol. 17, no. 8, 2021, pp. 1918-1933.
Tang M, Hu Z, Rao C, et al. Burkholderia pseudomallei interferes with host lipid metabolism via NR1D2-mediated PNPLA2/ATGL suppression to block autophagy-dependent inhibition of infection. Autophagy. 2021;17(8):1918-1933.
Tang, M., Hu, Z., Rao, C., Chen, J., Yuan, S., Zhang, J., Mao, C., Yan, J., Xia, Y., Zhang, M., Yue, J., Xiang, Y., Xie, J., Mao, X., & Li, Q. (2021). Burkholderia pseudomallei interferes with host lipid metabolism via NR1D2-mediated PNPLA2/ATGL suppression to block autophagy-dependent inhibition of infection. Autophagy, 17(8), 1918-1933. https://doi.org/10.1080/15548627.2020.1801270
Tang M, et al. Burkholderia Pseudomallei Interferes With Host Lipid Metabolism Via NR1D2-mediated PNPLA2/ATGL Suppression to Block Autophagy-dependent Inhibition of Infection. Autophagy. 2021;17(8):1918-1933. PubMed PMID: 32777979.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Burkholderia pseudomallei interferes with host lipid metabolism via NR1D2-mediated PNPLA2/ATGL suppression to block autophagy-dependent inhibition of infection. AU - Tang,Mengling, AU - Hu,Zhiqiang, AU - Rao,Chenglong, AU - Chen,Jiangao, AU - Yuan,Siqi, AU - Zhang,Jiangang, AU - Mao,Chan, AU - Yan,Jingmin, AU - Xia,Yupei, AU - Zhang,Meijuan, AU - Yue,Juanjuan, AU - Xiang,Yang, AU - Xie,Jianping, AU - Mao,Xuhu, AU - Li,Qian, Y1 - 2020/08/11/ PY - 2020/8/12/pubmed PY - 2022/1/18/medline PY - 2020/8/12/entrez KW - Autophagy KW - Burkholderia pseudomallei KW - NR1D2 KW - PNPLA2/ATGL KW - lipid droplet KW - lipid metabolism KW - lipophagy SP - 1918 EP - 1933 JF - Autophagy JO - Autophagy VL - 17 IS - 8 N2 - Burkholderia pseudomallei: which causes melioidosis with high mortality in humans, has become a global public health concern. Recently, infection-driven lipid droplet accumulation has been related to the progression of host-pathogen interactions, and its contribution to the pathogenesis of infectious disease has been investigated. Here, we demonstrated that B. pseudomallei infection actively induced a time-dependent increase in the number and size of lipid droplets in human lung epithelial cells and macrophages. We also found that lipid droplet accumulation following B. pseudomallei infection was associated with downregulation of PNPLA2/ATGL (patatin like phospholipase domain containing 2) and lipophagy inhibition. Functionally, lipid droplet accumulation, facilitated via PNPLA2 downregulation, inhibited macroautophagic/autophagic flux and, thus, hindered autophagy-dependent inhibition of B. pseudomallei infection in lung epithelial cells. Mechanistically, we further revealed that nuclear receptor NR1D2 might be involved in the suppression of PNPLA2 after cell exposure to B. pseudomallei. Taken together, our findings unraveled an evolutionary strategy, by which B. pseudomallei interferes with the host lipid metabolism, to block autophagy-dependent suppression of infection. This study proposes potential targets for clinical therapy of melioidosis.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; ATG7: autophagy related 7; B. pseudomallei: Burkholderia pseudomallei; CFU: colony-forming unit; DG: diglyceride; FASN: fatty acid synthase; GFP: green fluorescent protein; LAMP1: lysosomal associated membrane protein 1; LC-MS/MS: liquid chromatography-tandem mass spectrometry; LD: lipid droplet; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MG: monoglyceride; MOI: multiplicity of infection; mRFP: monomeric red fluorescent protein; NR1D2: nuclear receptor subfamily 1 group D member 2; p.i., post-infection; PLIN2/ADRP: perilipin 2; PNPLA2/ATGL: patatin like phospholipase domain containing 2; Rapa: rapamycin; SQSTM1/p62: sequestosome 1; shRNA: short hairpin RNA; TEM: transmission electron microscopy; TG: triglyceride. SN - 1554-8635 UR - https://www.unboundmedicine.com/medline/citation/32777979/Burkholderia_pseudomallei_interferes_with_host_lipid_metabolism_via_NR1D2_mediated_PNPLA2/ATGL_suppression_to_block_autophagy_dependent_inhibition_of_infection_ DB - PRIME DP - Unbound Medicine ER -