A synthetic biology approach identifies the mammalian UPR RNA ligase RtcB

Mol Cell. 2014 Sep 4;55(5):758-70. doi: 10.1016/j.molcel.2014.06.032. Epub 2014 Jul 31.


Signaling in the ancestral branch of the unfolded protein response (UPR) is initiated by unconventional splicing of HAC1/XBP1 mRNA during endoplasmic reticulum (ER) stress. In mammals, IRE1α has been known to cleave the XBP1 intron. However, the enzyme responsible for ligation of two XBP1 exons remains unknown. Using an XBP1 splicing-based synthetic circuit, we identify RtcB as the primary UPR RNA ligase. In RtcB knockout cells, XBP1 mRNA splicing is defective during ER stress. Genetic rescue and in vitro splicing show that the RNA ligase activity of RtcB is directly required for the splicing of XBP1 mRNA. Taken together, these data demonstrate that RtcB is the long-sought RNA ligase that catalyzes unconventional RNA splicing during the mammalian UPR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acyl-tRNA Synthetases
  • Animals
  • Base Sequence
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • Endoplasmic Reticulum / metabolism
  • Endoribonucleases / metabolism
  • Gene Knockout Techniques
  • Mice
  • Molecular Sequence Data
  • Protein Folding
  • Protein Serine-Threonine Kinases / metabolism
  • Proteins / chemistry
  • Proteins / genetics
  • Proteins / physiology*
  • RNA Interference
  • RNA Splicing / genetics*
  • Regulatory Factor X Transcription Factors
  • Sequence Alignment
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Unfolded Protein Response*
  • X-Box Binding Protein 1


  • DNA-Binding Proteins
  • Proteins
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • Ern1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Endoribonucleases
  • Amino Acyl-tRNA Synthetases
  • FAAP protein, mouse