Burkholderia pseudomallei interferes with host lipid metabolism via NR1D2-mediated PNPLA2/ATGL suppression to block autophagy-dependent inhibition of infection

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

Lipid Droplets, the Central Hub Integrating Cell Metabolism and the Immune System

“…The accumulation of LDs is related to host-pathogen interactions. NR1D2-mediated PNPLA2/ATGL inhibition disrupts the lipid metabolism of macrophages in the human body, leading to lipid accumulation and weakening the effect of autophagy on Burkholderia pseudomallei immunity to infection, leading to the continued development of infection (Tang et al, 2021). In Mycobacterium tuberculosis, the interaction between LDs and pathogen-containing phagosomes is controlled by mycobacterial cell wall components (LAM and PIM) and Intracellular free cholesterol (FC) can be transferred extracellular by ABCA1 to combine with extracellular apolipoprotein A1 (ApoA1) to form high-density lipoprotein (HDL).…”

A Novel Strategy for Identifying NSCLC MicroRNA Biomarkers and Their Mechanism Analysis Based on a Brand-New CeRNA-Hub-FFL Network

“…β-actin is a highly conserved cytoskeletal protein that commonly expresses and is essential for cell migration, mitosis, intracellular transport, and maintenance [ 35 ]. It has been considered an endogenous house-keeping gene and reference gene in cells and tissues for many years [ 36 ], which leads to its role in cancer being ignored. However, the emerging evidence suggests that ACTB expresses unstably and plays a key role in a variety of human diseases, particularly cancer [ 37 ].…”

The relationship between cholesterol metabolism and mitochondrial function in chronic obstructive pulmonary diseases

“…67 The increase in LDs in lung epithelial cells can be detected in bacterial infection, pulmonary cystic fibrosis and other lung diseases. 68,69 On the other hand, MFN2 knockdown impaired fatty acid oxidation in mitochondria, leading to excessive free fatty acids in the cytoplasm to synthesise triglycerides. Increased phosphatidic acids, the intermediate product in the process of triglyceride synthesis, 70 and phosphatidylcholine continuously disturbed lipid homeostasis in cells by activating the mTOR signalling pathway and forming positive feedback.…”

“…LDs maintain normal mitochondrial function by regulating the supply of fatty acids and maintaining fatty acid β‐oxidation by regulating the hydrolysis of triglycerides 67 . The increase in LDs in lung epithelial cells can be detected in bacterial infection, pulmonary cystic fibrosis and other lung diseases 68,69 . On the other hand, MFN2 knockdown impaired fatty acid oxidation in mitochondria, leading to excessive free fatty acids in the cytoplasm to synthesise triglycerides.…”