S6K2-mediated regulation of TRBP as a determinant of miRNA expression in human primary lymphatic endothelial cells

Abstract

MicroRNAs (miRNAs) are short non-coding RNAs that silence mRNAs. They are generated following transcription and cleavage by the DROSHA/DGCR8 and DICER/TRBP/PACT complexes. Although it is known that components of the miRNA biogenesis machinery can be phosphorylated, it remains poorly understood how these events become engaged during physiological cellular activation. We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. We demonstrate the functional relevance of this interaction in primary human dermal lymphatic endothelial cells (HDLECs). Angiopoietin-1 (ANG1) can augment miRNA biogenesis in HDLECs through enhancing TRBP phosphorylation and expression in an S6K2-dependent manner. We propose that the S6K2/TRBP node controls miRNA biogenesis in HDLECs and provides a molecular link between the mTOR pathway and the miRNA biogenesis machinery.

Metadata

Item Type:	Article
Authors/Creators:	Warner, Matthew J (mw1020@york.ac.uk) Bridge, Katherine S https://orcid.org/0000-0003-1516-1459 Hewitson, James P https://orcid.org/0000-0002-3265-6763 Hodgkinson, Michael R Heyam, Alex Massa, Bailey C Haslam, Jessica C Chatzifrangkeskou, Maria Evans, Gareth J O https://orcid.org/0000-0003-2573-7001 Plevin, Michael J https://orcid.org/0000-0003-2057-8291 Sharp, Tyson V Lagos, Dimitris https://orcid.org/0000-0003-0637-281X
Copyright, Publisher and Additional Information:	Funding Information: We would like to thank Banushan Balansethupathy for technical contributions. Wellcome Trust [097829; through the Centre for Chronic Diseases and Disorders at the University of York]; Medical Research Council [MR/L008505/1]; Yorkshire Cancer Research [TPP053 to D.L.]; BBSRC [BB/I007571/2 to T.V.S.]. 'Combating Infectious Disease: Computational Approaches in Translational Science' Wellcome Trust PhD programme [WT095024MA to A.P.H.]. Funding for open access charge: The University of York Open Access Fund through agreement with the Medical Research Council and The Wellcome Trust who funded the work. Conflict of interest statement. None declared. Publisher Copyright: © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.
Keywords:	Angiopoietin-1/pharmacology,Cell Line,Cells, Cultured,Endothelial Cells/drug effects,Gene Expression Regulation/drug effects,Humans,MicroRNAs/genetics,Phosphorylation,Protein Interaction Domains and Motifs,RNA-Binding Proteins/chemistry,Ribosomal Protein S6 Kinases/metabolism
Dates:	Published: 16 November 2016 Published (online): 12 July 2016 Accepted: 2 July 2016
Institution:	The University of York
Academic Units:	The University of York > Faculty of Sciences (York) > Centre for Immunology and Infection (CII) (York) The University of York > Faculty of Sciences (York) > Biology (York) The University of York > Faculty of Sciences (York) > Hull York Medical School (York)
Funding Information:	Funder Grant number BBSRC (BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL) UNSPECIFIED
Depositing User:	Pure (York)
Date Deposited:	12 Sep 2016 13:20
Last Modified:	26 Nov 2024 00:32
Published Version:	https://doi.org/10.1093/nar/gkw631
Status:	Published
Refereed:	Yes
Identification Number:	10.1093/nar/gkw631
Related URLs:	http://www.scopus.com/inward/record.url?...
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:104593

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S6K2-mediated regulation of TRBP as a determinant of miRNA expression in human primary lymphatic endothelial cells

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