Affiliation:
1. Divisions of Cancer Therapeutics and Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
Abstract
ABSTRACT
The unfolded protein response (UPR) remediates endoplasmic reticulum (ER) stress. IRE1, a component of the UPR, senses misfolded protein and cleaves
XBP1
mRNA, which is ligated to code for the prosurvival transcription factor. IRE1 also cleaves other mRNAs preceding their degradation, termed regulated IRE1-dependent mRNA decay (RIDD). It has been reported that RIDD may be involved in cell viability under stress and therefore may contribute to cancer cell viability. To investigate RIDD targets that may have functional relevance in cell survival, we identified conserved RIDD targets containing stringent IRE1 RNase target sequences. Using a systematic bioinformatics approach with quantitative-PCR (qPCR) validation, we show that only
BLOC1S1
is consistently a RIDD target in all systems tested. Using cancer cell lines, we show that
BLOC1S1
is specifically cleaved by IRE1 at guanine 444, but only under conditions of IRE1 hyperactivation.
BLOC1S1
cleavage is temporally separate from
XBP1
splicing, occurring after depletion of unspliced
XBP1
. Expression of an uncleavable
BLOC1S1
mutant or inhibition of RIDD using an IRE1 RNase inhibitor did not affect cellular recovery from acute ER stress. These data demonstrate that although hyperactivated IRE1 specifically cleaves
BLOC1S1
, this cleavage event and RIDD as a whole are dispensable for cell viability under acute stress.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
54 articles.
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