14-3-3τ regulates beclin 1 and is required for autophagy14-3-3τ调节需要beclin 1和自噬.pdfVIP

14-3-3t Regulates Beclin 1 and Is Required for Autophagy Bing Wang1., Shiyun Ling1,2., Weei-Chin Lin1,2* 1 Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America, 2 Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America Abstract Background: Beclin 1 plays an essential role in autophagy; however, the regulation of Beclin 1 expression remains largely unexplored. An earlier ChIP-on-chip study suggested Beclin 1 could be an E2F target. Previously, we also reported that 14-3- 3t regulates E2F1 stability, and is required for the expression of several E2F1 target genes. 14-3-3 proteins mediate many cellular signaling processes, but its role in autophagy has not been investigated. We hypothesize that 14-3-3t could regulate Beclin 1 expression through E2F1 and thus regulate autophagy. Methods and Findings: Using the RNAi technique we demonstrate a novel role for one of 14-3-3 isoforms, 14-3-3t, in the regulation of Beclin 1 expression and autophagy. Depletion of 14-3-3t inhibits the expression of Beclin 1 in many different cell lines; whereas, upregulation of 14-3-3t induces Beclin 1. The regulation is physiologically relevant as an extracellular matrix protein tenascin-C, a known 14-3-3t inducer, can induce Beclin 1 through 14-3-3t. Moreover, rapamycin-induced, serum free-induced and amino acid starvation-induced autophagy depends on 14-3-3t. We also show the expression of Beclin 1 depends on E2F, and E2F can transactivate the Beclin 1 promoter in a promoter reporter assay. Upregulation of Beclin 1 by 14-3-3t requires E2F1. Depletion of E2F1, like 14-3-3t, also inhibits autophagy. Conclusion: Taken together, this study uncovers a role for 14-3-3t in Beclin 1 and autophagy regulation probably through regulation of E2F1. Citation