Bcl-xL inhibits tBid and Bax via distinct mechanisms,Faraday Discussions

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Bcl-xL inhibits tBid and Bax via distinct mechanisms
Faraday Discussions ( IF 3.3 ) Pub Date : 2020-07-07 , DOI: 10.1039/d0fd00045k
Fabronia Murad ₁ , Ana J Garcia-Saez _{1,

2}

Affiliation

The proteins of the Bcl-2 family are key regulators of apoptosis. They form a complex interaction network in the cytosol and in cellular membranes, whose outcome determines mitochondrial permeabilization and commitment to death. However, we still do not understand how the action of the different family members is orchestrated to regulate apoptosis. Here, we combined quantitative analysis of the interactions and the localization dynamics of the family representatives Bcl-xL, Bax and tBid, in living cells. We discovered that Bax and tBid are able to constitutively shuttle between cytosol and mitochondria in the absence of other Bcl-2 proteins. Bcl-xL clearly stabilized tBid at mitochondria, where they formed tight complexes. In contrast, Bcl-xL promoted Bax retrotranslocation to the cytosol without affecting its shuttling rate, but by forming weak inhibitory mitochondrial complexes. Furthermore, analysis of phospho-mimetics of Bcl-xL suggested that phosphorylation regulates the function of Bcl-xL via multiple mechanisms. Altogether, our findings support a model in which the Bcl-2 network not only modulates protein/protein interactions among the family members, but also their respective intracellular localization dynamics, to regulate apoptosis.

中文翻译：

Bcl-xL 通过不同的机制抑制 tBid 和 Bax

Bcl-2 家族的蛋白质是细胞凋亡的关键调节因子。它们在胞质溶胶和细胞膜中形成复杂的相互作用网络，其结果决定了线粒体通透性和对死亡的承诺。然而，我们仍然不了解不同家族成员的行动是如何协调来调节细胞凋亡的。在这里，我们结合了家族代表 Bcl-xL、Bax 和 tBid 在活细胞中的相互作用和定位动力学的定量分析。我们发现在没有其他 Bcl-2 蛋白的情况下，Bax 和 tBid 能够组成性地在细胞质和线粒体之间穿梭。Bcl-xL 明显稳定了线粒体的 tBid，在那里它们形成了紧密的复合物。相比之下，Bcl-xL 在不影响其穿梭速率的情况下促进 Bax 逆向转运至胞质溶胶，但通过形成弱抑制性线粒体复合物。此外，对 Bcl-xL 的磷酸模拟物的分析表明，磷酸化调节了 Bcl-xL 的功能通过多种机制。总之，我们的研究结果支持一个模型，其中 Bcl-2 网络不仅调节家族成员之间的蛋白质/蛋白质相互作用，而且还调节它们各自的细胞内定位动力学，以调节细胞凋亡。

更新日期：2020-07-07

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