title: Selective autophagy degrades DICER and AGO2 and regulates miRNA activity.
abstract: MicroRNAs (miRNAs) form a class of short RNAs (∼ 21 nucleotides) that post-transcriptionally regulate partially complementary messenger RNAs. Each miRNA may target tens to hundreds of transcripts to control key biological processes. Although the biochemical reactions underpinning miRNA biogenesis and activity are relatively well defined and the importance of their homeostasis is increasingly evident, the processes underlying regulation of the miRNA pathway in vivo are still largely elusive. Autophagy, a degradative process in which cytoplasmic material is targeted into double-membrane vacuoles, is recognized to critically contribute to cellular homeostasis. Here, we show that the miRNA-processing enzyme, DICER (also known as DICER1), and the main miRNA effector, AGO2 (also known as eukaryotic translation initiation factor 2C, 2 (EIF2C2)), are targeted for degradation as miRNA-free entities by the selective autophagy receptor NDP52 (also known as calcium binding and coiled-coil domain 2 (CALCOCO2)). Autophagy establishes a checkpoint required for continued loading of miRNA into AGO2; accordingly, NDP52 and autophagy are required for homeostasis and activity of the tested miRNAs. Autophagy also engages post-transcriptional regulation of the DICER mRNA, underscoring the importance of fine-tuned regulation of the miRNA pathway. These findings have implications for human diseases linked to misregulated autophagy, DICER- and miRNA-levels, including cancer.
authors.affiliation: Swiss Federal Institute of Technology (ETH-Z), Department of Biology, Zürich 8092, Switzerland.
authors.forename: Derrick
authors.initials: D
authors.lastname: Gibbings
authors.forename: Serge
authors.initials: S
authors.lastname: Mostowy
authors.forename: Florence
authors.initials: F
authors.lastname: Jay
authors.forename: Yannick
authors.initials: Y
authors.lastname: Schwab
authors.forename: Pascale
authors.initials: P
authors.lastname: Cossart
authors.forename: Olivier
authors.initials: O
authors.lastname: Voinnet
mesh_terms: D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D035683:MicroRNAs / Q000378:metabolism*; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; C094297:CALCOCO2 protein, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D043244:Ribonuclease III