Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms

Cell. 2015 May 21;161(5):1058-1073. doi: 10.1016/j.cell.2015.04.029.

Abstract

Regnase-1 and Roquin are RNA binding proteins essential for degradation of inflammation-related mRNAs and maintenance of immune homeostasis. However, their mechanistic relationship has yet to be clarified. Here, we show that, although Regnase-1 and Roquin regulate an overlapping set of mRNAs via a common stem-loop structure, they function in distinct subcellular locations: ribosome/endoplasmic reticulum and processing-body/stress granules, respectively. Moreover, Regnase-1 specifically cleaves and degrades translationally active mRNAs and requires the helicase activity of UPF1, similar to the decay mechanisms of nonsense mRNAs. In contrast, Roquin controls translationally inactive mRNAs, independent of UPF1. Defects in both Regnase-1 and Roquin lead to large increases in their target mRNAs, although Regnase-1 tends to control the early phase of inflammation when mRNAs are more actively translated. Our findings reveal that differential regulation of mRNAs by Regnase-1 and Roquin depends on their translation status and enables elaborate control of inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Codon, Terminator
  • HeLa Cells
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Mice
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Nucleic Acid Conformation
  • Polyribosomes / metabolism
  • Protein Biosynthesis
  • RNA Stability*
  • RNA, Messenger / chemistry
  • RNA, Messenger / metabolism*
  • Ribonucleases / metabolism*
  • Ribosomal Proteins / metabolism
  • Trans-Activators / metabolism
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Codon, Terminator
  • RNA, Messenger
  • Rent1 protein, mouse
  • Ribosomal Proteins
  • Trans-Activators
  • Rc3h1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Ribonucleases
  • Zc3h12a protein, mouse