一種新型長鏈非編碼 RNA BCRP3 通過激活自噬促進蛋白質穩態和細胞存活

Abstract

長鏈非編碼 RNA(LncRNA) 能調節許多生物反應，最近研究發現 lncRNAs 在自噬調節中扮演重要作用。然而目前對 lncRNAs 調控自噬的機制尚不清楚。本研究中，我們發現一種新型 lncRNA BCRP3 在多種腫瘤中的表達異常低，並做為自噬的正調節因子。進一步我們確認 BCRP3 主要位於細胞質中並能提高 VPS34 活性來啟動自噬。當細胞處於蛋白毒性刺激下會促進 BCRP3 的基因表現，進而促進泛素化蛋白質聚集體的清除。當蛋白質毒性刺激下， BCRP3 缺乏不僅影響蛋白質動態平衡的調節，還導致 TGF-β/Smad2 訊號被啟動，最後造成生長抑制、細胞凋亡。總上所述，我們研究揭示了 BCRP3 通過增強 Vps34 複合物的活性進而促進自噬作用來維持蛋白質動態平衡和細胞存活。

Long noncoding RNAs (LncRNAs) have been implicated in regulating many biological processes. Recent studies have also shown that lncRNAs play important roles in autophagy regulation. However, the underlying mechanism of lncRNAs in autophagy has not been unveiled. In this study, we identified a novel lncRNA BCRP3 as a positive modulator of autophagy and with abnormally low expression in a variety of tumors. BCRP3 is mainly located in the cytoplasm and binds to the VPS34 complex, which in turn initiates autophagy under basal and starvation conditions. In response to proteasome inhibition or oxidative stress-induced proteotoxicity, BCRP3 is upregulated to promote autophagy, thus facilitating the clearance of ubiquitinated protein aggregates. BCRP3 deficiency under proteotoxic stress not only comprises the protein quality control, but also leads to growth inhibition, cell death, and apoptosis. These cell survival defects are mediated in part through the upregulation of the TGF-/Smad2 pathway. In conclusion, our study revealed the role of BCRP3 as a positive regulator of autophagy by binding to VPS34 complex and BCRP3 is important for the maintenance of protein homeostasis and cell survival.