the e1b19k oncoprotein complexes with beclin 1 to regulate autophagy in adenovirus-infected cellse1b19k的癌蛋白复合物beclin 1调节自噬在adenovirus-infected细胞.pdfVIP

The E1B19K Oncoprotein Complexes with Beclin 1 to Regulate Autophagy in Adenovirus-Infected Cells 1 1 1 1 2 Sujan Piya , Erin J. White , Sarah R. Klein , Hong Jiang , Timothy J. McDonnell , Candelaria Gomez- Manzano1,3*, Juan Fueyo1,3* 1 Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America, 2 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America, 3 Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America Abstract The mechanisms underlying adenovirus-mediated autophagy are currently unknown. Recently, members of the Bcl-2 protein family have been associated with autophagy. It was also reported that the Bcl-2 homology-3 (BH3) domain encompassed by both Beclin 1 and Bcl-2-like proteins is essential for their pro-autophagy or anti-autophagy functions. Here, we report for the first time that E1B19K, the adenovirus BH3 domain protein, interacts with Beclin 1 to initiate autophagy. Using immunoprecipitation assays we showed that expression of E1B19K in the host cell disrupted the physical interactions between Beclin 1 and Bcl-2 proteins. The displacement of Bcl-2 was coincident with the recruitment of PI3KC3 to the Beclin 1/E1B19K complexes. As a result of the changes in the components of the Beclin 1 interactome, there was activation of PI3KC3, as showed by the identification of PI3K-mediated lipid phosphorylation, and subsequent formation of autophagosomes. Importantly, the BH3 functional domain of E1B19K protein was required for the heterodimerization with Beclin 1. We also showed that transfer of E1B