Cholesterol Binds in a Reversed Orientation to TCRβ-TM in Which Its OH Group is Localized to the Center of the Lipid Bilayer

Wu, Hongyi; Cao, Ruiyu; Wei, Shukun; Pathan-Chhatbar, Salma; Wen, Mingwu; Wu, Bin; Schamel, Wolfgang W. A.; Wang, Shuqing; OuYang, Bo

doi:10.1016/j.jmb.2021.167328

Cited by 6 publications

(7 citation statements)

References 58 publications

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“…3, B and C ). To more precisely identify the cholesterol binding site(s), two spin-labeled cholesterol derivatives, 3β-DOXYL-5α-cholestane (DOXYL-CH) and 25-doxyl-cholesterol (CNO) ( 33 ), were used to measure PRE effects on PD-L1-TC ( Fig. 3D ).…”

Section: Resultsmentioning

confidence: 99%

“…DOXYL-CH and CNO titrations were performed as previously described ( 33 ). Briefly, we mixed PD-L1-TC and DMPC with spin-labeled cholesterol derivatives in each of the organic solvents, dried the solution under a nitrogen stream, lyophilized overnight to remove the organic solvent, and then dissolved the mixture in NMR buffer (25 mM MES, pH 6.5) with DH 6 PC.…”

Section: Methodsmentioning

confidence: 99%

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Regulation of PD-L1 through direct binding of cholesterol to CRAC motifs

et al. 2022

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Cholesterol, an essential molecule for cell structure, function, and viability, plays crucial roles in the development, progression, and survival of cancer cells. Earlier studies have shown that cholesterol-lowering drugs can inhibit the high expression of programmed-death ligand 1 (PD-L1) that contributes to immunoevasion in cancer cells. However, the regulatory mechanism of cell surface PD-L1 abundance by cholesterol is still controversial. Here, using nuclear magnetic resonance and biochemical techniques, we demonstrated that cholesterol can directly bind to the transmembrane domain of PD-L1 through two cholesterol-recognition amino acid consensus (CRAC) motifs, forming a sandwich-like architecture and stabilizing PD-L1 to prevent downstream degradation. Mutations at key binding residues prohibit PD-L1–cholesterol interactions, decreasing the cellular abundance of PD-L1. Our results reveal a unique regulatory mechanism that controls the stability of PD-L1 in cancer cells, providing an alternative method to overcome PD-L1–mediated immunoevasion in cancers.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Regulation of PD-L1 through direct binding of cholesterol to CRAC motifs

et al. 2022

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“…Cellular and PM cholesterol homeostasis, and by extension mevalonate metabolism, has been shown to influence antigen receptor signaling in the plasma membrane. In the absence of antigen recognition, cholesterol has been shown to specifically bind to the transmembrane (TM) region of the TCR, 82,[89][90][91] which stabilizes the TCR in an inactive state (Figure 3). 92 Lowering cholesterol levels, either by treatment with cholesterol oxidase or MβCD treatment, increases the proportion of TCRs in the active conformational state.…”

Section: Cholesterol Allosterically Regulates Tcr Triggeringmentioning

confidence: 99%

Decoding the crosstalk between mevalonate metabolism and T cell function

Kennewick

Bensinger

2023

Immunological Reviews

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SummaryThe mevalonate pathway is an essential metabolic pathway in T cells regulating development, proliferation, survival, differentiation, and effector functions. The mevalonate pathway is a complex, branched pathway composed of many enzymes that ultimately generate cholesterol and nonsterol isoprenoids. T cells must tightly control metabolic flux through the branches of the mevalonate pathway to ensure sufficient isoprenoids and cholesterol are available to meet cellular demands. Unbalanced metabolite flux through the sterol or the nonsterol isoprenoid branch is metabolically inefficient and can have deleterious consequences for T cell fate and function. Accordingly, there is tight regulatory control over metabolic flux through the branches of this essential lipid synthetic pathway. In this review we provide an overview of how the branches of the mevalonate pathway are regulated in T cells and discuss our current understanding of the relationship between mevalonate metabolism, cholesterol homeostasis and T cell function.

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“…Intrathymic injection of CS leads to the DP cells' apoptosis through attenuating TCR sensitivity to the survival signals from self‐pMHC ligands. This is largely attributed to the fact that CS disrupted the TCR multimers by competing and replacing cholesterol bound to TCRβ within a CARC‐like cholesterol recognition motif 75 . Strikingly, elevated cholesterol levels enhance the elimination of the self‐reactive thymocyte cells via the negative selection of the Sult2b1 −/− mice 74 .…”

Section: Cholesterol Metabolism Is Involved In the T‐cell Aging Processmentioning

confidence: 99%

“…Recent evidence also suggests that Tfam fl/fl CD4‐Cre mice exhibit a higher production of inflammatory cytokines (TNF) and the significant upregulation of senescent‐associated genes in the liver, heart, white adipose tissue, and pancreas due to the metabolic dysfunction 91 . Similarly, the activity of senescence‐associated β‐galactosidase is also elevated, suggesting that the aberrant metabolism of T cells accelerates organismal dyshomeostasis 75 . Collectively, cholesterol is directly associated with inflamm‐aging and T‐cell senescence.…”

Section: Cholesterol Metabolism Is Involved In the T‐cell Aging Processmentioning

confidence: 99%

Cholesterol metabolism in T‐cell aging: Accomplices or victims

Zhu

et al. 2023

The FASEB Journal

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Aging has a significant impact on the function and metabolism of T cells. Cholesterol, the most important sterol in mammals, is known as the “gold of the body” because it maintains membrane fluidity, rigidity, and signal transduction while also serving as a precursor of oxysterols, bile acids, and steroid hormones. Cholesterol homeostasis is primarily controlled by uptake, biosynthesis, efflux, and regulatory mechanisms. Previous studies have suggested that there are reciprocal interactions between cholesterol metabolism and T lymphocytes. Here, we will summarize the most recent advances in the effects of cholesterol and its derivatives on T‐cell aging. We will furthermore discuss interventions that might be used to help older individuals with immune deficiencies or diminishing immune competence.

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Cholesterol Binds in a Reversed Orientation to TCRβ-TM in Which Its OH Group is Localized to the Center of the Lipid Bilayer

Cited by 6 publications

References 58 publications

Regulation of PD-L1 through direct binding of cholesterol to CRAC motifs

Regulation of PD-L1 through direct binding of cholesterol to CRAC motifs

Decoding the crosstalk between mevalonate metabolism and T cell function

Cholesterol metabolism in T‐cell aging: Accomplices or victims

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