IRE1beta-mediated cell death pathways unraveled

IRE1b is the less well known brother of IRE1a, the most conserved member of the unfolded protein

response (UPR). IRE1a is an endonuclease that splices Xbp1 mRNA to generate Xbp1s, encoding a

potent transcription factor in the UPR. Besides, IRE1a can also degrade other mRNAs in a process

termed RIDD. The functions of IRE1b are less established. In contrast to IRE1a that shows a

ubiquitous expression pattern, IRE1b expression is restricted to epithelial cells lining the mucosa of

the gut and lung, and data from mouse show that IRE1b is involved in mucus production.

Mechanistically, IRE1b would perform its functions via RIDD rather than XBP1s splicing. Other

reports claim that IRE1b is a regulator of IRE1a, without having its own unique function. In humans,

it is unclear how IRE1b expression is regulated. Several studies showed that overexpression of IRE1b

is toxic in cells, although it is unclear what causes cell death. In order to probe the function of IRE1b,

we generated an inducible expression system in human colon cell lines. We confirmed the dosedependent

toxicity and cell killing upon IRE1b expression and found that cells could be rescued by

an IRE1 endonuclease inhibitor, suggesting that IRE1b-mediated killing was RIDD dependent. In the

current project, we aim to identify pathways underlying IRE1-mediated cell death. We believe this

will provide important information hinting to its possible function and regulation in human cells.