Graduate School of Science and Technology, Shizuoka University, Ohya 836, Suruga-ku, Shizuoka, 422-8021, Japan.
Department of Bioscience, Faculty of Science, Shizuoka University, Ohya 836, Suruga-ku, Shizuoka, 422-8021, Japan.
Biochem Biophys Res Commun. 2021 May 7;552:1-8. doi: 10.1016/j.bbrc.2021.03.033. Epub 2021 Mar 16.
The degradation of nucleolar proteins - nucleophagy - is elicited by nutrient starvation or the inactivation of target of rapamycin complex 1 (TORC1) protein kinase in budding yeast. Prior to nucleophagy, nucleolar proteins migrate to the nucleus-vacuole junction (NVJ), where micronucleophagy occurs, whereas rDNA (rRNA gene) repeat regions are condensed and escape towards NVJ-distal sites. This suggests that the NVJ controls nucleolar dynamics from outside of the nucleus after TORC1 inactivation, but its molecular mechanism is unclear. Here, we show that sorting nexin (SNX) Mdm1, an inter-organelle tethering protein at the NVJ, mediates TORC1 inactivation-induced nucleolar dynamics. Furthermore, Mdm1 was required for proper nucleophagic degradation of nucleolar proteins after TORC1 inactivation, where it was dispensable for the induction of nucleophagic flux itself. This indicated that nucleophagy and nucleolar dynamics are independently regulated by TORC1 inactivation. Finally, Mdm1 was critical for survival during nutrient starvation conditions. Mutations of SNX14, a human Mdm1 homolog, cause neurodevelopmental disorders. This study provides a novel insight into relationship between sorting nexin-mediated microautophagy and neurodevelopmental disorders.
核仁蛋白的降解——核噬作用——是由营养饥饿或芽殖酵母中雷帕霉素靶蛋白复合物 1（TORC1）蛋白激酶失活引起的。在核噬作用之前，核仁蛋白迁移到核-液泡连接点（NVJ），在这里发生微核噬作用，而 rDNA（rRNA 基因）重复区则浓缩并向 NVJ 远端区域逃逸。这表明，TORC1 失活后，NVJ 从核外控制核仁动力学，但它的分子机制尚不清楚。在这里，我们表明分选连接蛋白（SNX）Mdm1 作为 NVJ 上的一种细胞器间连接蛋白，介导 TORC1 失活诱导的核仁动力学。此外，Mdm1 对于 TORC1 失活后核仁蛋白的适当核噬降解是必需的，而对于核噬通量的诱导本身则是可有可无的。这表明核噬作用和核仁动力学是由 TORC1 失活独立调节的。最后，Mdm1 在营养饥饿条件下对生存至关重要。人类 Mdm1 同源物 SNX14 的突变会导致神经发育障碍。本研究为分选连接蛋白介导的微自噬与神经发育障碍之间的关系提供了新的见解。
