Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis.
Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis.
复制标题
核糖体蛋白 S27 样通过 β-TrCP-DEPTOR-mTORC1 轴调节自噬。
DOI：
10.1038/s41419-018-1168-7
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发表时间：
2018-11-13
影响因子：
9
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Xiong X;Liu X;Li H;He H;Sun Y;Zhao Y
RPS 27 L（RibosomalProteinS 27-like）是一种进化上保守的核糖体蛋白，是p53的靶蛋白和生理性p53调节剂。我们以前报道过Rps 27 l破坏通过触发基因组不稳定性增强Trp 53 +/−小鼠的淋巴瘤发生，并通过阻断DNA损伤反应使Trp 53 +/−小鼠对辐射敏感。RPS 27 L是否以及如何调节自噬是完全未知的。在这里，我们报告说，RPS 27 L沉默显着诱导自噬乳腺癌MB 231和SK-BR 3细胞窝藏突变p53。从机制上讲，RPS 27 L沉默显著灭活了mTORC 1，一种主要的负性自噬调节因子，但不是mTORC 2。自噬诱导和mTORC 1失活也观察到与Rps 27 l缺失的MEFs。更具体地说，RPS 27 L沉默缩短了β-TrCP的蛋白半衰期，β-TrCP是Skp 1-Cullin 1-F-box（SCF）遍在蛋白连接酶的底物受体，负责DEPTOR降解，导致DEPTOR积累以抑制mTORC 1活性。此外，RPS 27 L沉默诱导的自噬和mTORC 1失活可以通过同时DEPTOR沉默部分挽救，表明DEPTOR的因果作用。在生物学上，自噬抑制剂氯喹（CQ）或巴弗洛霉素A1（BAF A1）显著诱导RPS 27 L沉默细胞的凋亡，表明自噬是响应RPS 27 L缺失的细胞存活机制。最后，与邻近的正常组织相比，人类乳腺癌中的RPS 27 L水平降低。总的来说，我们的研究表明，RPS 27 L减少可能通过β-TrCP-DEPTOR-mTORC 1轴诱导自噬在乳腺肿瘤发生过程中起促进作用。
RPS27L (Ribosomal protein S27-like), an evolutionarily conserved ribosomal protein, is a p53 target and a physiological p53 regulator. We previously reported that Rps27l disruption enhanced lymphomagenesis in Trp53+/− mice by triggering genome instability and sensitized Trp53+/− mice to radiation by blocking DNA damage response. Whether and how RPS27L modulates autophagy is totally unknown. Here we report that RPS27L silencing significantly induced autophagy in breast cancer MB231 and SK-BR3 cells harboring mutant p53. Mechanistically, RPS27L silencing remarkably inactivated mTORC1, a major negative autophagy regulator, but not mTORC2. Autophagy induction and mTORC1 inactivation was also observed in MEFs with Rps27l deletion. More specifically, RPS27L silencing shortened the protein half-life of β-TrCP, a substrate receptor of Skp1-Cullin 1-F-box (SCF) ubiquitin ligase, which is responsible for DEPTOR degradation, leading to DEPTOR accumulation to inhibit mTORC1 activity. Furthermore, RPS27L silencing-induced autophagy and mTORC1 inactivation can be partially rescued by simultaneous DEPTOR silencing, suggesting a causal role of DEPTOR. Biologically, autophagy inhibitor, chloroquine (CQ), or Bafilomycin A1 (BAF A1), significantly induced apoptosis in RPS27L silenced cells, indicating that autophagy is a cellular survival mechanism in response to RPS27L loss. Finally, RPS27L levels were reduced in human breast cancers, as compared to adjacent normal tissues. Collectively, our study suggests that RPS27L reduction might play a promoting role during breast tumorigenesis by autophagy induction via the β-TrCP-DEPTOR-mTORC1 axis.
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