Mammalian hyperplastic discs Homolog EDD Regulates miRNA-Mediated Gene Silencing

Hong Su; Shuxia Meng; Yanyan Lu; Melanie I. Trombly; Jian Chen; Chengyi Lin; Anita Turk; Xiaozhong Wang

doi:10.1016/j.molcel.2011.06.013

Mammalian hyperplastic discs Homolog EDD Regulates miRNA-Mediated Gene Silencing

Hong Su, Shuxia Meng, Yanyan Lu, Melanie I. Trombly, Jian Chen, Chengyi Lin, Anita Turk, Xiaozhong Wang^*

^*Corresponding author for this work

Molecular Biosciences

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

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.

Original language	English (US)
Pages (from-to)	97-109
Number of pages	13
Journal	Molecular cell
Volume	43
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2011.06.013
State	Published - Jul 8 2011

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2011.06.013

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@article{09eb83997faa4beeaca76ea49a5b6512,

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.",

author = "Hong Su and Shuxia Meng and Yanyan Lu and Trombly, {Melanie I.} and Jian Chen and Chengyi Lin and Anita Turk and Xiaozhong Wang",

note = "Funding Information: We thank M.J. Henderson and C.K. Watts for human EDD cDNA, E. Izaurralde for various TNRC6A constructs, S. Krobitsch for human ATXN2 cDNA and M. Kiriakidou for anti-Ago (2A8) antibody. This work was supported by grants from NIGMS (5R21GM079528) and NU-PSOC (under 5U45CA143869) to X.W. ",

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AU - Trombly, Melanie I.

AU - Chen, Jian

AU - Lin, Chengyi

AU - Turk, Anita

AU - Wang, Xiaozhong

N1 - Funding Information: We thank M.J. Henderson and C.K. Watts for human EDD cDNA, E. Izaurralde for various TNRC6A constructs, S. Krobitsch for human ATXN2 cDNA and M. Kiriakidou for anti-Ago (2A8) antibody. This work was supported by grants from NIGMS (5R21GM079528) and NU-PSOC (under 5U45CA143869) to X.W.

PY - 2011/7/8

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N2 - 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.

AB - 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.

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Mammalian hyperplastic discs Homolog EDD Regulates miRNA-Mediated Gene Silencing

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