A Synthetic Biology Approach Identifies the Mammalian UPR RNA Ligase RtcB

Yanyan Lu, Feng Xia Liang, Xiaozhong Wang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

147 Scopus citations


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 invitro 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.

Original languageEnglish (US)
Pages (from-to)758-770
Number of pages13
JournalMolecular cell
Issue number5
StatePublished - 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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