# Direct optical activation of human IRE1 identifies unique patterns of transcriptional and post-transcriptional mRNA regulation in the unfolded protein response

## TL;DR

Researchers used light to activate IRE1 in human cells, revealing new insights into how IRE1 regulates mRNA during the unfolded protein response.

## Contribution

A light-activatable IRE1 tool was developed to study its specific role in the UPR without interference from other stress sensors.

## Key findings

- IRE1 activation in human cells occurs through oligomerization alone.
- Prolonged IRE1 activation leads to evolving transcriptional responses.
- The UPR changes mRNA splice isoform abundance independently of IRE1.

## Abstract

Inositol-requiring enzyme 1 (IRE1) is one of the three known sensor proteins that respond to homeostatic perturbations in the metazoan endoplasmic reticulum. The three sensors collectively initiate an intertwined signaling network called the unfolded protein response (UPR). Although IRE1 plays pivotal roles in human health and development, understanding its specific contributions to the UPR remains a challenge due to signaling crosstalk from the other two stress sensors. To overcome this problem, we engineered a light-activatable version of IRE1 and probed the transcriptomic effects of IRE1 activity in isolation from the other branches of the UPR. We demonstrate that 1) oligomerization alone is sufficient to activate IRE1 in human cells, 2) IRE1’s transcriptional response evolves substantially under prolonged activation, and 3) the UPR induces major changes in mRNA splice isoform abundance in an IRE1-independent manner. Our data reveal previously unknown targets of IRE1’s transcriptional regulation and direct degradation. Additionally, the tools developed here will be broadly applicable for precise dissection of the UPR in diverse cell types, tissues, and organisms.