Sequestration of misfolded proteins into distinct cellular compartments plays a pivotal role in proteostasis and proteopathies. Cytoplasmic ubiquitinated proteins are sequestered by p62/SQSTM1 to deposit in sequestosomes or aggresome-like induced structures (ALIS). Most aggresome or ALIS regulators identified thus far are recruiters, while little is known about the disaggregases or dissolvers. In this research, we showed that lanosterol synthase and its enzymatic product lanosterol effectively reduced the number and/or size of sequestosomes/ALIS/aggresomes formed by endogenous proteins in the HeLa and HEK-293A cells cultured under both non-stressed and stressed conditions. Supplemented lanosterol did not affect the proteasome and autophagic activities, but released the trapped proteins from the p62-positive inclusions accompanied with the activation of HSF1 and up-regulation of various heat shock proteins. Our results suggested that the coordinated actions of disaggregation by lanosterol and refolding by heat shock proteins might facilitate the cells to recycle proteins from aggregates. The disaggregation activity of lanosterol was not shared by cholesterol, indicating that lanosterol possesses additional cellular functions in proteostasis regulation. Our findings highlight that besides protein modulators, the cells also possess endogenous low-molecular-weight compounds as efficient proteostasis regulators.

中文翻译：

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羊毛甾醇通过溶解胞质螯合体/类似脂质体的诱导结构来调节蛋白稳态。

将错误折叠的蛋白质隔离到不同的细胞区室中，在蛋白稳定和蛋白病中起关键作用。细胞质泛素化蛋白被p62 / SQSTM1隔离，沉积在隔离体或类似聚集体的诱导结构（ALIS）中。到目前为止，确定的大多数综合性或ALIS监管者都是招募人员，而对分解物或溶解剂知之甚少。在这项研究中，我们显示了羊毛甾醇合酶及其酶促产物羊毛甾醇可有效减少HeLa和HEK-293A细胞在非应激和应激条件下培养的内源性蛋白质形成的螯合物/ ALIS /聚集体的数量和/或大小。补充的羊毛甾醇不会影响蛋白酶体和自噬活性，但会从p62阳性内含物中释放出被捕获的蛋白质，并伴随着HSF1的激活和各种热休克蛋白的上调。我们的研究结果表明，羊毛甾醇的分解作用和热激蛋白重新折叠的协同作用可能促进细胞从聚集物中回收蛋白质。胆固醇不具有羊毛脂的分解活性，这表明羊毛脂在蛋白稳态调节中还具有其他细胞功能。我们的发现突出表明，除蛋白质调节剂外，细胞还具有内源性低分子量化合物作为有效的蛋白稳态调节剂。我们的研究结果表明，羊毛甾醇的分解作用和热激蛋白重新折叠的协同作用可能促进细胞从聚集物中回收蛋白质。胆固醇不具有羊毛脂的分解活性，这表明羊毛脂在蛋白稳态调节中还具有其他细胞功能。我们的发现突出表明，除蛋白质调节剂外，细胞还具有内源性低分子量化合物作为有效的蛋白稳态调节剂。我们的研究结果表明，羊毛甾醇的分解作用和热激蛋白重新折叠的协同作用可能促进细胞从聚集物中回收蛋白质。胆固醇不具有羊毛脂的分解活性，这表明羊毛脂在蛋白稳态调节中还具有其他细胞功能。我们的发现突出表明，除蛋白质调节剂外，细胞还具有内源性低分子量化合物作为有效的蛋白稳态调节剂。