14-3-3τ Regulates Beclin 1 and Is Required for Autophagy

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 14-3-3tau 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 14-3-3tau 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, 14-3-3tau, in the regulation of Beclin 1 expression and autophagy. Depletion of 14-3-3tau inhibits the expression of Beclin 1 in many different cell lines; whereas, upregulation of 14-3-3tau induces Beclin 1. The regulation is physiologically relevant as an extracellular matrix protein tenascin-C, a known 14-3-3tau inducer, can induce Beclin 1 through 14-3-3tau. Moreover, rapamycin-induced, serum free-induced and amino acid starvation-induced autophagy depends on 14-3-3tau. 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 14-3-3tau requires E2F1. Depletion of E2F1, like 14-3-3tau, also inhibits autophagy.CONCLUSION: Taken together, this study uncovers a role for 14-3-3tau in Beclin 1 and autophagy regulation probably through regulation of E2F1.