title: Mammalian hyperplastic discs homolog EDD regulates miRNA-mediated gene silencing.
abstract: MicroRNAs (miRNAs) regulate gene expression through translation repression and mRNA destabilization. However, the molecular mechanisms of miRNA silencing are still not well defined. Using a genetic screen in mouse embryonic stem (ES) cells, we identify mammalian hyperplastic discs protein EDD, a known E3 ubiquitin ligase, as a key component of the miRNA silencing pathway. ES cells deficient for EDD are defective in miRNA function and exhibit growth defects. We demonstrate that E3 ubiquitin ligase activity is dispensable for EDD function in miRNA silencing. Instead, EDD interacts with GW182 family proteins in the Argonaute-miRNA complexes. The PABC domain of EDD is essential for its silencing function. Through the PABC domain, EDD participates in miRNA silencing by recruiting downstream effectors. Among the PABC-interactors, DDX6 and Tob1/2 are both required and sufficient for silencing mRNA targets. Taken together, these data demonstrate a critical function for EDD in miRNA silencing.
authors: Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA.
authors: Hong
authors: H
authors: Su
authors: Shuxia
authors: S
authors: Meng
authors: Yanyan
authors: Y
authors: Lu
authors: Melanie I
authors: MI
authors: Trombly
authors: Jian
authors: J
authors: Chen
authors: Chengyi
authors: C
authors: Lin
authors: Anita
authors: A
authors: Turk
authors: Xiaozhong
authors: X
authors: Wang
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000378:metabolism; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C490903:Tob1 protein, mouse; C489244:UBR5 protein, mouse; D044767:Ubiquitin-Protein Ligases; C490616:Ddx6 protein, mouse; D053487:DEAD-box RNA Helicases