RRC ID 61092
Author Mino T, Iwai N, Endo M, Inoue K, Akaki K, Hia F, Uehata T, Emura T, Hidaka K, Suzuki Y, Standley DM, Okada-Hatakeyama M, Ohno S, Sugiyama H, Yamashita A, Takeuchi O.
Title Translation-dependent unwinding of stem-loops by UPF1 licenses Regnase-1 to degrade inflammatory mRNAs.
Journal Nucleic Acids Res
Abstract Regnase-1-mediated mRNA decay (RMD), in which inflammatory mRNAs harboring specific stem-loop structures are degraded, is a critical part of proper immune homeostasis. Prior to initial translation, Regnase-1 associates with target stem-loops but does not carry out endoribonucleolytic cleavage. Single molecule imaging revealed that UPF1 is required to first unwind the stem-loops, thus licensing Regnase-1 to proceed with RNA degradation. Following translation, Regnase-1 physically associates with UPF1 using two distinct points of interaction: The Regnase-1 RNase domain binds to SMG1-phosphorylated residue T28 in UPF1; in addition, an intrinsically disordered segment in Regnase-1 binds to the UPF1 RecA domain, enhancing the helicase activity of UPF1. The SMG1-UPF1-Regnase-1 axis targets pioneer rounds of translation and is critical for rapid resolution of inflammation through restriction of the number of proteins translated by a given mRNA. Furthermore, small-molecule inhibition of SMG1 prevents RNA unwinding in dendritic cells, allowing post-transcriptional control of innate immune responses.
Volume 47(16)
Pages 8838-8859
Published 2019-9-19
DOI 10.1093/nar/gkz628
PII 5536979
PMID 31329944
PMC PMC7145602
MeSH Animals Fibroblasts / cytology Fibroblasts / immunology HEK293 Cells HeLa Cells Homeostasis / genetics Homeostasis / immunology Humans Immunity, Innate Inflammation Inverted Repeat Sequences Macrophages / cytology Macrophages / immunology Macrophages, Peritoneal / cytology Macrophages, Peritoneal / immunology* Mice Mice, Knockout Mutation Nonsense Mediated mRNA Decay / immunology* Primary Cell Culture Protein Binding Protein Biosynthesis Protein Interaction Domains and Motifs Protein Serine-Threonine Kinases / genetics* Protein Serine-Threonine Kinases / immunology RNA, Messenger / genetics* RNA, Messenger / metabolism Ribonucleases / deficiency Ribonucleases / genetics* Ribonucleases / immunology Single Molecule Imaging Trans-Activators / genetics* Trans-Activators / immunology
IF 11.502
DNA material pFLAG-mRegnase-1-WT (RDB18148) pFLAG-mRegnase-1-D141N (RDB18149) pFLAG-mRegnase-1-KR257258AA (KRAA) (RDB18150) pFLAG-mRoquin-1-WT (RDB18151) pmCherry-mRegnase-1-(90-400)-D141N (RDB18152) pmCherry-mRegnase-1-(130-400)-D141N (RDB18153) pmRegnase-1-(130-300)-D141N-L2-mCherryX2-C1 (RDB18154) pmRegnase-1-(3000-400)-L2-mCherryX2-C1 (RDB18155) pTRE-mIL6CDS-mIL63'UTR (RDB18156) pGL3-mIL6-3'UTR (RDB18157) pGL3-mPtgs2-3'UTR (RDB18158)