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Gibbings D.,ETH Zurich | Gibbings D.,University of Ottawa | Mostowy S.,Institute Pasteur Paris | Mostowy S.,French Institute of Health and Medical Research | And 9 more authors.
Nature Cell Biology | Year: 2012

MicroRNAs (miRNAs) form a class of short RNAs (∼ 21â €‰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. © 2012 Macmillan Publishers Limited. All rights reserved.

Tromas A.,Institute des science du Vegetal ISV | Tromas A.,Agriculture and Agri Food Canada | Paque S.,Institute des science du Vegetal ISV | Stierle V.,Institute des science du Vegetal ISV | And 6 more authors.
Nature Communications | Year: 2013

Auxin is a major plant hormone that controls most aspects of plant growth and development. Auxin is perceived by two distinct classes of receptors: transport inhibitor response 1 (TIR1, or auxin-related F-box (AFB)) and auxin/indole-3-acetic acid (AUX/IAA) coreceptors, that control transcriptional responses to auxin, and the auxin-binding protein 1 (ABP1), that controls a wide variety of growth and developmental processes. To date, the mode of action of ABP1 is still poorly understood and its functional interaction with TIR1/AFB-AUX/IAA coreceptors remains elusive. Here we combine genetic and biochemical approaches to gain insight into the integration of these two pathways. We find that ABP1 is genetically upstream of TIR1/AFBs; ABP1 knockdown leads to an enhanced degradation of AUX/IAA repressors, independently of its effects on endocytosis, through the SCF TIR1/AFB E3 ubiquitin ligase pathway. Combining positive and negative regulation of SCF ubiquitin-dependent pathways might be a common mechanism conferring tight control of hormone-mediated responses. © 2013 Macmillan Publishers Limited. All rights reserved.

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