Translation-dependent unwinding of stem-loops by UPF1 licenses Regnase-1 to degrade inflammatory mRNAs

Nucleic Acids Res. 2019 Sep 19;47(16):8838-8859. doi: 10.1093/nar/gkz628.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • RNA, Messenger
  • Rent1 protein, mouse
  • Trans-Activators
  • Protein Serine-Threonine Kinases
  • Smg1 protein, mouse
  • Ribonucleases
  • Zc3h12a protein, mouse