Regulation of exosome release by lysosomal acid ceramidase in coronary arterial endothelial cells: Role of TRPML1 channel.

4区 生物学 Q4 Biochemistry, Genetics and Molecular Biology Current topics in membranes Pub Date : 2022-01-01 DOI:10.1016/bs.ctm.2022.09.002
Guangbi Li, Dandan Huang, Pengyang Li, Xinxu Yuan, Viktor Yarotskyy, Pin-Lan Li
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Abstract

Lysosomal acid ceramidase (AC) has been reported to determine multivesicular body (MVB) fate and exosome secretion in different mammalian cells including coronary arterial endothelial cells (CAECs). However, this AC-mediated regulation of exosome release from CAECs and associated underlying mechanism remain poorly understood. In the present study, we hypothesized that AC controls lysosomal Ca2+ release through TRPML1 channel to regulate exosome release in murine CAECs. To test this hypothesis, we isolated and cultured CAECs from WT/WT and endothelial cell-specific Asah1 gene (gene encoding AC) knockout mice. Using these CAECs, we first demonstrated a remarkable increase in exosome secretion and significant reduction of lysosome-MVB interaction in CAECs lacking Asah1 gene compared to those cells from WT/WT mice. ML-SA1, a TRPML1 channel agonist, was found to enhance lysosome trafficking and increase lysosome-MVB interaction in WT/WT CAECs, but not in CAECs lacking Asah1 gene. However, sphingosine, an AC-derived sphingolipid, was able to increase lysosome movement and lysosome-MVB interaction in CAECs lacking Asah1 gene, leading to reduced exosome release from these cells. Moreover, Asah1 gene deletion was shown to substantially inhibit lysosomal Ca2+ release through suppression of TRPML1 channel activity in CAECs. Sphingosine as an AC product rescued the function of TRPML1 channel in CAECs lacking Asah1 gene. These results suggest that Asah1 gene defect and associated deficiency of AC activity may inhibit TRPML1 channel activity, thereby reducing MVB degradation by lysosome and increasing exosome release from CAECs. This enhanced exosome release from CAECs may contribute to the development of coronary arterial disease under pathological conditions.

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溶酶体酸性神经酰胺酶对冠状动脉内皮细胞外泌体释放的调节:TRPML1通道的作用。
据报道,溶酶体酸神经酰胺酶(AC)在包括冠状动脉内皮细胞(CAECs)在内的不同哺乳动物细胞中决定多泡体(MVB)的命运和外泌体的分泌。然而,这种ac介导的caec外泌体释放调控及其相关的潜在机制仍然知之甚少。在本研究中,我们假设AC通过TRPML1通道控制溶酶体Ca2+释放,以调节小鼠caec中的外泌体释放。为了验证这一假设,我们从WT/WT和内皮细胞特异性Asah1基因(编码AC的基因)敲除小鼠中分离并培养caec。使用这些caec,我们首先证明了与来自WT/WT小鼠的细胞相比,缺乏Asah1基因的caec中外泌体分泌显著增加,溶酶体- mvb相互作用显著减少。ML-SA1是一种TRPML1通道激动剂,在WT/WT caec中可以增强溶酶体运输并增加溶酶体与mvb的相互作用,但在缺乏Asah1基因的caec中则没有。然而,在缺乏Asah1基因的caec中,鲨鞘脂(一种ac衍生的鞘脂)能够增加溶酶体的运动和溶酶体- mvb的相互作用,从而减少这些细胞的外泌体释放。此外,Asah1基因缺失被证明通过抑制caec中TRPML1通道活性来显著抑制溶酶体Ca2+释放。鞘氨醇作为一种AC产物,在缺乏Asah1基因的caec中恢复了TRPML1通道的功能。这些结果表明,Asah1基因缺陷和相关的AC活性缺乏可能抑制TRPML1通道活性,从而减少溶酶体对MVB的降解,增加caec的外泌体释放。caec的外泌体释放增强可能有助于病理条件下冠状动脉疾病的发展。
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来源期刊
Current topics in membranes
Current topics in membranes 生物-生化与分子生物学
CiteScore
3.50
自引率
0.00%
发文量
10
审稿时长
>12 weeks
期刊介绍: Current Topics in Membranes provides a systematic, comprehensive, and rigorous approach to specific topics relevant to the study of cellular membranes. Each volume is a guest edited compendium of membrane biology.
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