Entangling roles of cholesterol-dependent interaction and cholesterol-mediated lipid phase heterogeneity in regulating listeriolysin O pore-formation.

IF 4.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemical Journal Pub Date : 2024-09-13 DOI:10.1042/bcj20240184
Kusum Lata,Gregor Anderluh,Kausik Chattopadhyay
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Abstract

Cholesterol-dependent cytolysins (CDCs) are the distinct class of β-barrel pore-forming toxins (β-PFTs) that attack eukaryotic cell membranes, and form large, oligomeric, transmembrane β-barrel pores. Listeriolysin O (LLO) is a prominent member in the CDC family. As documented for the other CDCs, membrane cholesterol is essential for the pore-forming functionality of LLO. However, it remains obscure how exactly cholesterol facilitates its pore formation. Here, we show that cholesterol promotes both membrane-binding and oligomerization of LLO. We demonstrate cholesterol not only facilitates membrane-binding, it also enhances the saturation threshold of LLO-membrane association, and alteration of the cholesterol-recognition motif (CRM) in the LLO mutant (LLOT515G-L516G) compromises its pore-forming efficacy. Interestingly, such defect of LLOT515G-L516G could be rescued in the presence of higher membrane cholesterol levels, suggesting cholesterol can augment the pore-forming efficacy of LLO even in the absence of a direct toxin-cholesterol interaction. Furthermore, we find the membrane-binding and pore-forming abilities of LLOT515G-L516G, but not those of LLO, correlate with the cholesterol-dependent rigidity/ordering of the membrane lipid bilayer. Our data further suggest that the line tension derived from the lipid phase heterogeneity of the cholesterol-containing membranes could play a pivotal role in LLO function, particularly in the absence of cholesterol binding. Therefore, in addition to its receptor-like role, we conclude cholesterol can further facilitate the pore-forming, membrane-damaging functionality of LLO by asserting the optimal physicochemical environment in membranes. To the best of our knowledge, this aspect of the cholesterol-mediated regulation of the CDC mode of action has not been appreciated thus far.
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胆固醇依赖性相互作用和胆固醇介导的脂相异质性在调节李斯特溶菌素 O 孔隙形成中的纠缠作用。
胆固醇依赖性细胞溶解素(CDCs)是一类独特的β管孔形成毒素(β-PFTs),可攻击真核细胞膜,并形成大型、寡聚、跨膜的β管孔。李斯特溶菌素 O(LLO)是 CDC 家族中的一个重要成员。根据其他 CDC 的记录,膜胆固醇对 LLO 的孔形成功能至关重要。然而,胆固醇究竟是如何促进其孔隙形成的仍不清楚。在这里,我们发现胆固醇能促进 LLO 的膜结合和寡聚化。我们证明胆固醇不仅能促进膜结合,还能提高 LLO 与膜结合的饱和阈值,而 LLO 突变体(LLOT515G-L516G)中胆固醇识别基序(CRM)的改变会影响其孔形成的功效。有趣的是,在膜胆固醇水平较高的情况下,LLOT515G-L516G 的这种缺陷可以被挽救,这表明即使在毒素与胆固醇没有直接相互作用的情况下,胆固醇也能增强 LLO 的成孔效能。此外,我们还发现 LLOT515G-L516G 的膜结合能力和孔形成能力与胆固醇依赖的膜脂双层刚性/有序性相关,而 LLO 则不然。我们的数据进一步表明,来自含胆固醇膜脂相异质性的线张力可能在 LLO 功能中发挥关键作用,尤其是在没有胆固醇结合的情况下。因此,除了类似于受体的作用之外,我们还得出结论,胆固醇可以通过在膜中形成最佳的物理化学环境,进一步促进 LLO 的孔形成和膜破坏功能。据我们所知,胆固醇介导的 CDC 作用模式的这方面调控迄今尚未得到重视。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biochemical Journal
Biochemical Journal 生物-生化与分子生物学
CiteScore
8.00
自引率
0.00%
发文量
255
审稿时长
1 months
期刊介绍: Exploring the molecular mechanisms that underpin key biological processes, the Biochemical Journal is a leading bioscience journal publishing high-impact scientific research papers and reviews on the latest advances and new mechanistic concepts in the fields of biochemistry, cellular biosciences and molecular biology. The Journal and its Editorial Board are committed to publishing work that provides a significant advance to current understanding or mechanistic insights; studies that go beyond observational work using in vitro and/or in vivo approaches are welcomed. Painless publishing: All papers undergo a rigorous peer review process; however, the Editorial Board is committed to ensuring that, if revisions are recommended, extra experiments not necessary to the paper will not be asked for. Areas covered in the journal include: Cell biology Chemical biology Energy processes Gene expression and regulation Mechanisms of disease Metabolism Molecular structure and function Plant biology Signalling
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