# RNA Ligation Pathways in Mammalian Unfolded Protein Response

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $303,712

## Abstract

Project Summary
The unfolded protein response (UPR), a well-known adaptive mechanism for cells to maintain
ER homeostasis, has been implicated in the pathogenesis of a variety of human diseases.
Genetic deletion of the UPR signaling components can significantly influence the disease
progression in mouse models for diabetes, hepatic steatosis, IBD, ALS and other diseases. We
have recently performed a synthetic biology screen to interrogate the mammalian UPR pathway.
From this screen, we have identified RtcB as a long sought RNA ligase that catalyzes
unconventional XBP-1 splicing during ER stress. RtcB is a multifunctional RNA ligase that also
acts in tRNA splicing. Genetic rescue of RtcB knockout cells suggests that RtcB-mediated
ligation of XBP1 and tRNA may occur at different subcellular compartments. We will therefore
determine subcellular compartment-specific RtcB function. By generating Trpt1 and RtcB double
knockout cells and performing genetic rescue, we further demonstrate that a second
biochemically distinct RNA ligation pathway cooperates with RtcB in mammalian cells to
regulate XBP1 and tRNA splicing. Therefore, we will examine the role of other putative
components in the RNA ligation pathway. Lastly we will identify unknown RNA ligases of the
new ligation pathway by a genetic suppressor screen using RtcB knockout cells. By revealing
the complete molecular repertoire of RNA ligation pathways, we will hopefully gain new insights
and uncover new therapeutic targets to modulate the mammalian UPR.

## Key facts

- **NIH application ID:** 9959445
- **Project number:** 5R01GM120307-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** XIAOZHONG ALEC WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $303,712
- **Award type:** 5
- **Project period:** 2017-09-30 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959445

## Citation

> US National Institutes of Health, RePORTER application 9959445, RNA Ligation Pathways in Mammalian Unfolded Protein Response (5R01GM120307-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9959445. Licensed CC0.

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