Molecular basis for the recognition of 24-(S)-hydroxycholesterol by integrin αvβ3.
Molecular basis for the recognition of 24-(S)-hydroxycholesterol by integrin αvβ3.
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DOI：
10.1038/s41598-023-36040-4
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发表时间：
2023-06-06
影响因子：
4.6
通讯作者：
Natesan, Senthil
中科院分区：
文献类型：
--
作者：
Gc, Jeevan B.;Chen, Justin;Pokharel, Swechha M.;Mohanty, Indira;Mariasoosai, Charles;Obi, Peter;Panipinto, Paul;Bandyopadhyay, Smarajit;Bose, Santanu;Natesan, Senthil
越来越多的证据表明，25-羟基胆固醇（25HC）等氧甾醇具有生物活性，并参与许多生理和病理过程。我们之前的研究表明，25HC通过激活整合素黏附激酶（FAK）途径在病毒感染过程中诱导先天免疫反应。25HC通过在新的结合位点（II位点）直接与整合素结合，并触发促炎介质如肿瘤坏死因子-α (TNF)和白细胞介素-6 （IL-6）的产生，从而产生促炎反应。24-(S)-羟基胆固醇（24HC）是25HC的一种结构异构体，在人脑胆固醇稳态中起关键作用，并与包括阿尔茨海默病在内的多种炎症有关。然而，在非神经元细胞中，24HC是否能像25HC一样诱导促炎反应还没有研究，仍然是未知的。本研究的目的是通过计算机和体外实验来检验24HC是否会产生这样的免疫反应。我们的研究结果表明，尽管24HC是25HC的结构异构体，但24HC以不同的结合模式结合在II位点，参与不同的残基相互作用，并在特异性决定环（SDL）中产生显著的构象变化。此外，我们的表面等离子体共振（SPR）研究表明，24HC可以直接结合整合素αvβ3，其结合亲和力比25HC低3倍。此外，我们对巨噬细胞的体外研究支持FAK和NFκB信号通路参与触发24hc介导的TNF生成。因此，我们已经确定24HC是另一种结合整合素αvβ3并通过整合素- fak - nfκ b途径促进促炎反应的氧甾醇。
A growing body of evidence suggests that oxysterols such as 25-hydroxycholesterol (25HC) are biologically active and involved in many physiological and pathological processes. Our previous study demonstrated that 25HC induces an innate immune response during viral infections by activating the integrin-focal adhesion kinase (FAK) pathway. 25HC produced the proinflammatory response by binding directly to integrins at a novel binding site (site II) and triggering the production of proinflammatory mediators such as tumor necrosis factor-α (TNF) and interleukin-6 (IL-6). 24-(S)-hydroxycholesterol (24HC), a structural isomer of 25HC, plays a critical role in cholesterol homeostasis in the human brain and is implicated in multiple inflammatory conditions, including Alzheimer’s disease. However, whether 24HC can induce a proinflammatory response like 25HC in non-neuronal cells has not been studied and remains unknown. The aim of this study was to examine whether 24HC produces such an immune response using in silico and in vitro experiments. Our results indicate that despite being a structural isomer of 25HC, 24HC binds at site II in a distinct binding mode, engages in varied residue interactions, and produces significant conformational changes in the specificity-determining loop (SDL). In addition, our surface plasmon resonance (SPR) study reveals that 24HC could directly bind to integrin αvβ3, with a binding affinity three-fold lower than 25HC. Furthermore, our in vitro studies with macrophages support the involvement of FAK and NFκB signaling pathways in triggering 24HC-mediated production of TNF. Thus, we have identified 24HC as another oxysterol that binds to integrin αvβ3 and promotes a proinflammatory response via the integrin-FAK-NFκB pathway.
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DOI：
10.3390/antiox10050740
发表时间：
2021-05-07
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Gamba P;Giannelli S;Staurenghi E;Testa G;Sottero B;Biasi F;Poli G;Leonarduzzi G
通讯作者：
Leonarduzzi G
DOI：
10.1016/j.str.2017.09.007
发表时间：
2017-11-07
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Borst AJ;James ZM;Zagotta WN;Ginsberg M;Rey FA;DiMaio F;Backovic M;Veesler D
通讯作者：
Veesler D
DOI：
10.1073/pnas.0909142106
发表时间：
2009-09-29
影响因子：
11.1
作者：
Bauman, David R.;Bitmansour, Andrew D.;Russell, David W.
通讯作者：
Russell, David W.
DOI：
10.1073/pnas.1404271111
发表时间：
2014-07-22
影响因子：
11.1
作者：
Gold, Elizabeth S.;Diercks, Alan H.;Aderem, Alan
通讯作者：
Aderem, Alan
影响因子：
14.5
作者：
Djelti, Fathia;Braudeau, Jerome;Cartier, Nathalie
通讯作者：
Cartier, Nathalie