Inhibition of retroviral Gag assembly by non-silencing miRNAs promotes autophagic viral degradation  

作　　者：Na Qu Zhao Ma Mengrao Zhang Muaz N. Rushdi Christopher J. Krueger Antony K. Chen 

机构地区：[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

出　　处：《Protein & Cell》2018年第7期640-651,共12页蛋白质与细胞（英文版）

摘　　要：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-medi- ated Gag assembly at the plasma membrane. Conse- quently, misassembled viral complexes are redirected into the endocytic pathway where they are delivered to lysosomes for degradation. In this study, we demon- strate 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 endo- somesllysosomes, demonstrating a convergence of autophagy with functional degradative compartments. Knocking down autophagosome formation machineries reduced this convergence, while treatment with autop- hagy-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 non- specific 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 possi- bility that similar regulations can occur in other biolog- ical contexts.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-medi- ated Gag assembly at the plasma membrane. Conse- quently, misassembled viral complexes are redirected into the endocytic pathway where they are delivered to lysosomes for degradation. In this study, we demon- strate 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 endo- somesllysosomes, demonstrating a convergence of autophagy with functional degradative compartments. Knocking down autophagosome formation machineries reduced this convergence, while treatment with autop- hagy-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 non- specific 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 possi- bility that similar regulations can occur in other biolog- ical contexts.

关 键 词：microRNA Gag protein AUTOPHAGY 

分 类 号：Q522[生物学—生物化学] S858.317.4[农业科学—临床兽医学]