Tumor susceptibility gene 101 (TSG101), an ESCRT-I protein, is implicated in multiple cellular processes and its functional depletion can lead to blocked lysosomal degradation, cell cycle arrest, demyelination and neurodegeneration. Here, we show that loss of TSG101 results in endoplasmic reticulum (ER) stress and this causes ER membrane remodelling (EMR). This correlates with an expansion of ER, increased vacuolation, altered relative distribution of the rough and smooth ER and disruption of three-way junctions. Blocked lysosomal degradation due to TSG101 depletion leads to ER stress and Ca²⁺ leakage from ER stores, causing destabilization of actin cytoskeleton. Inhibiting Ca²⁺ release from the ER by blocking ryanodine receptors (RYRs) with Dantrolene partially rescues the ER stress phenotypes. Hence, in this study we have identified the involvement of TSG101 in modulating ER stress mediated remodelling by engaging the actin cytoskeleton. This is significant because functional depletion of TSG101 effectuates ER-stress, perturbs the structure, mobility and function of the ER, all aspects closely associated with neurodegenerative diseases.

Summary statement

We show that tumor susceptibility gene (TSG) 101 regulates endoplasmic reticulum (ER) stress and its membrane remodelling. Loss of TSG101 perturbs structure, mobility and function of the ER as a consequence of actin destabilization.

中文翻译：

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肿瘤易感基因101（TSG101）的丢失扰乱了内质网的结构和功能。

肿瘤易感基因101（TSG101）是一种ESCRT-1蛋白，涉及多个细胞过程，其功能耗竭可导致溶酶体降解受阻，细胞周期停滞，脱髓鞘和神经变性。在这里，我们显示TSG101的丢失导致内质网（ER）应力，这会导致ER膜重塑（EMR）。这与ER的扩展，空泡增加，粗糙和光滑的ER的相对分布改变以及三向连接的破坏有关。由于TSG101耗竭而导致的溶酶体降解受阻，导致内质网应激和内质网的Ca ²⁺泄漏，从而导致肌动蛋白细胞骨架失稳。抑制Ca ²⁺通过用丹特罗阻断ryanodine受体（RYRs）从ER中释放出来可以部分挽救ER应激表型。因此，在这项研究中，我们已经确定了TSG101通过参与肌动蛋白细胞骨架而参与调节ER应激介导的重塑。这是很重要的，因为TSG101的功能衰竭会影响内质网应激，扰乱内质网的结构，活动性和功能，而这些方面都与神经退行性疾病密切相关。

摘要声明

我们表明，肿瘤易感基因（TSG）101调节内质网（ER）压力及其膜重塑。由于肌动蛋白不稳定，TSG101的丧失会干扰ER的结构，活动性和功能。