Mevalonate Pathway Regulates Cell Size Homeostasis and Proteostasis through Autophagy.
Mevalonate Pathway Regulates Cell Size Homeostasis and Proteostasis through Autophagy.
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DOI：
10.1016/j.celrep.2015.11.045
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发表时间：
2015-12-22
期刊：
影响因子：
8.8
通讯作者：
Björklund M
中科院分区：
文献类型：
--
作者：
Miettinen TP;Björklund M
细胞生长和增殖之间的平衡决定了细胞大小的内稳态，但对代谢途径如何参与维持这种平衡知之甚少。在这里，我们对临床使用的药物分子库进行筛选，以了解它们对细胞大小的影响。我们发现他汀类药物，甲羟戊酸途径抑制剂，减少细胞增殖，增加细胞大小和细胞蛋白密度在各种细胞类型，包括原代人细胞。甲羟戊酸途径对细胞大小和蛋白质密度的影响是通过小GTPase RAB11的香叶酰化介导的，这是基础自噬通量所必需的。我们的研究结果确定甲羟戊酸途径是自噬的代谢调节剂，并揭示了细胞大小和蛋白质停滞调节中的一个悖论，其中抑制合成代谢途径会导致细胞大小和细胞蛋白质密度的增加。甲羟戊酸途径调节细胞大小、增殖和细胞蛋白密度RAB11的Geranylgeranylation将甲羟戊酸途径与自噬联系起来甲羟戊酸途径是基础自噬通量所必需的细胞大小和蛋白密度效应依赖于RAB11和自噬细胞大小的控制是正常细胞功能所必需的。Miettinen和Björklund发现甲羟戊酸途径调节哺乳动物细胞的基础自噬通量，他们表明抑制这种代谢途径会增加细胞大小，出乎意料地增加细胞蛋白质密度。
Balance between cell growth and proliferation determines cell size homeostasis, but little is known about how metabolic pathways are involved in the maintenance of this balance. Here, we perform a screen with a library of clinically used drug molecules for their effects on cell size. We find that statins, inhibitors of the mevalonate pathway, reduce cell proliferation and increase cell size and cellular protein density in various cell types, including primary human cells. Mevalonate pathway effects on cell size and protein density are mediated through geranylgeranylation of the small GTPase RAB11, which is required for basal autophagic flux. Our results identify the mevalonate pathway as a metabolic regulator of autophagy and expose a paradox in the regulation of cell size and proteostasis, where inhibition of an anabolic pathway can cause an increase in cell size and cellular protein density. Mevalonate pathway regulates cell size, proliferation, and cellular protein density Geranylgeranylation of RAB11 links mevalonate pathway to autophagy Mevalonate pathway is required for basal autophagic flux Cell size and protein density effects are dependent on RAB11 and autophagy Control of cell size is essential for normal cell functions. Miettinen and Björklund find that the mevalonate pathway regulates basal autophagic flux in mammalian cells, and they show that inhibition of this metabolic pathway increases cell size and, unexpectedly, cellular protein density.