Format

Send to

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

A synthetic biology approach identifies the mammalian UPR RNA ligase RtcB.

Author information

1
Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA.
2
Office of Collaborative Science Microscopy Core, New York University School of Medicine, New York, NY 10016, USA.
3
Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA. Electronic address: awang@northwestern.edu.

Abstract

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.

PMID:
25087875
PMCID:
PMC4156904
DOI:
10.1016/j.molcel.2014.06.032
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center