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Uncovering lipopolysaccharide regulation in bacteria via the critical lipid binding tunnel of YciS/YciM.

ABSTRACT: Gram-negative bacteria contain an asymmetric outer membrane, in which the outer leaflet is composed of lipopolysaccharide (LPS). LPS, a drug target of polymyxin, plays an essential role in drug resistance, biofilm formation, and pathogenesis. An important inner membrane protein, YciM, may be responsible for the regulation of LPS biosynthesis and transport. Here, we report the crystal structure of YciM from Salmonella typhimurium in a complex with a non-specifically bond molecule, an ethylene glycol, which identified a tunnel that could bind lipids. Our in vitro assays showed that YciM could bind lipid molecules with affinity in the micromolar range, while mutagenic and functional studies confirmed that lipid-binding residues are critical for the function of YciM. Additionally, our data also showed that YciM accurately regulates LPS biosynthesis and transport with YciS, which could help to better understand the regulation mechanism of LPS.

SUBMITTER: Yan L

PROVIDER: S-EPMC9460159 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Uncovering lipopolysaccharide regulation in bacteria via the critical lipid binding tunnel of YciS/YciM.

Yan Lina L Dong Haohao H Li Huanyu H Liu Xingyu X Deng Zixin Z Dong Changjiang C Zhang Zhengyu Z

iScience 20220820 9

Gram-negative bacteria contain an asymmetric outer membrane, in which the outer leaflet is composed of lipopolysaccharide (LPS). LPS, a drug target of polymyxin, plays an essential role in drug resistance, biofilm formation, and pathogenesis. An important inner membrane protein, YciM, may be responsible for the regulation of LPS biosynthesis and transport. Here, we report the crystal structure of YciM from <i>Salmonella typhimurium</i> in a complex with a non-specifically bond molecule, an ethyl ...[more]

PMID: 36093049

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Project description:BackgroundAtherosclerosis is a chronic degenerative disease of the arteries and is thought to be one of the most common causes of death globally. In recent years, the functions of adventitial fibroblasts in the development of atherosclerosis and tissue repair have gained increased interests. LPS can increase the morbidity and mortality of atherosclerosis-associated cardiovascular disease. Although LPS increases neointimal via TLR4 activation has been reported, how LPS augments atherogenesis through acting on adventitial fibroblasts is still unknown. Here we explored lipid deposition within adventitial fibroblasts mediated by lipopolysaccharide (LPS) to imitate inflammatory conditions.ResultsIn our study, LPS enhanced lipid deposition by the up-regulated expression of adipose differentiation-related protein (ADRP) as the silencing of ADRP abrogated lipid deposition in LPS-activated adventitial fibroblasts. In addition, pre-treatment with anti-Toll-like receptor 4 (TLR4) antibody diminished the LPS-induced lipid deposition and ADRP expression. Moreover, LPS induced translocation of nuclear factor-κB (NF-κB), which could markedly up-regulate lipid deposition as pre-treatment with the NF-κB inhibitor, PDTC, significantly reduced lipid droplets. In addition, the lowering lipid accumulation was accompanied with the decreased ADRP expression. Furthermore, LPS-induced adventitial fibroblasts secreted more monocyte chemoattractant protein (MCP-1), compared with transforming growth factor-β1 (TGF-β1).ConclusionsTaken together, these results suggest that LPS promotes lipid accumulation via the up-regulation of ADRP expression through TLR4 activated downstream of NF-κB in adventitial fibroblasts. Increased levels of MCP-1 released from LPS-activated adventitial fibroblasts and lipid accumulation may accelerate monocytes recruitment and lipid-laden macrophage foam cells formation. Here, our study provides a new explanation as to how bacterial infection contributes to the pathological process of atherosclerosis.

Dataset Information

Uncovering lipopolysaccharide regulation in bacteria via the critical lipid binding tunnel of YciS/YciM.

Publications

Uncovering lipopolysaccharide regulation in bacteria via the critical lipid binding tunnel of YciS/YciM.

Similar Datasets

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