1] Center for Translational Cancer Research, Institute for Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, USA [2].
Nat Cell Biol. 2013 Oct;15(10):1186-96. doi: 10.1038/ncb2822. Epub 2013 Aug 18.
Subcellular localization is emerging as an important mechanism for mTORC1 regulation. We report that the tuberous sclerosis complex (TSC) signalling node, TSC1, TSC2 and Rheb, localizes to peroxisomes, where it regulates mTORC1 in response to reactive oxygen species (ROS). TSC1 and TSC2 were bound by peroxisomal biogenesis factors 19 and 5 (PEX19 and PEX5), respectively, and peroxisome-localized TSC functioned as a Rheb GTPase-activating protein (GAP) to suppress mTORC1 and induce autophagy. Naturally occurring pathogenic mutations in TSC2 decreased PEX5 binding, and abrogated peroxisome localization, Rheb GAP activity and suppression of mTORC1 by ROS. Cells lacking peroxisomes were deficient in mTORC1 repression by ROS, and peroxisome-localization-deficient TSC2 mutants caused polarity defects and formation of multiple axons in neurons. These data identify a role for the TSC in responding to ROS at the peroxisome, and identify the peroxisome as a signalling organelle involved in regulation of mTORC1.
细胞内定位正在成为 mTORC1 调节的一个重要机制。我们报告称，结节性硬化复合物（TSC）信号节点 TSC1、TSC2 和 Rheb 定位于过氧化物酶体，在过氧化物酶体中，它可以响应活性氧（ROS）来调节 mTORC1。TSC1 和 TSC2 分别与过氧化物酶体生物发生因子 19 和 5（PEX19 和 PEX5）结合，过氧化物酶体定位的 TSC 作为 Rheb GTP 酶激活蛋白（GAP）发挥作用，抑制 mTORC1 并诱导自噬。TSC2 中的天然致病性突变降低了 PEX5 的结合，并消除了过氧化物酶体的定位、Rheb GAP 活性以及 ROS 对 mTORC1 的抑制作用。缺乏过氧化物酶体的细胞对 ROS 引起的 mTORC1 抑制作用不足，并且过氧化物酶体定位缺陷的 TSC2 突变体导致神经元中的极性缺陷和多个轴突的形成。这些数据表明 TSC 在过氧化物酶体中对 ROS 作出反应的作用，并确定过氧化物酶体是参与调节 mTORC1 的信号细胞器。
