Zhao Ma
Mengrao Zhang
Muaz N. Rushdi
Christopher J. Krueger
Antony K. Chen
1 Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China;
2 Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
Funds: This project was supported by grants from the National Key R&D Program of China (2016YFA0501603 and 2016YFA0100702), the National Natural Science Foundation of China (Grant No. 81371613), the Beijing Natural Science Foundation (7162114) and China's 1000 Young Talent Award program. We thank Dr. Ying-Chun Hu for her professional technical assistance in EM sample preparation and image analysis at the Core Facilities of College of Life Sciences, Peking University.
Received Date: 2017-06-30
Rev Recd Date:2017-08-07
Abstract
Abstract
We recently reported an unconventional mechanism by which miRNAs inhibit HIV-1 viral production. This occurs when miRNAs bind nonspecifically to the viral structural protein Gag, interfering with viral RNA-mediated Gag assembly at the plasma membrane. Consequently, misassembled viral complexes are redirected into the endocytic pathway where they are delivered to lysosomes for degradation. In this study, we demonstrate that autophagy is a critical mediator of the viral degradation pathway and that this pathway is not HIV-1 specific. Misassembled viral complexes were found to colocalize extensively with LC3 and p62 in late endosomes/lysosomes, demonstrating a convergence of autophagy with functional degradative compartments. Knocking down autophagosome formation machineries reduced this convergence, while treatment with autophagy-inducer rapamycin enhanced the convergence. Furthermore, similar autophagy-dependent nonspecific miRNA inhibition of murine leukemia virus (MLV) assembly was shown. Overall, these results reveal autophagy as a crucial regulator of the retroviral degradation pathway in host cells initiated by nonspecific miRNA-Gag interactions. These findings could have significant implications for understanding how cells may regulate retroviral complex assembly by miRNA expression and autophagy, and raise the possibility that similar regulations can occur in other biological contexts.Keywords: microRNA,
Gag protein,
autophagy
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