Under irremediable ER stress, IRE1α's RNase triggers the rapid decay of select microRNAs that normally repress translation of Caspase-2 mRNA, rapidly increasing Caspase-2 levels as the first step in its activation. 818, published online 4 October) now report that IRE1α is the ER stress sensor that activates Caspase-2, and does so through a mechanism involving non-coding RNAs. However, the molecular events leading from the detection of ER stress to Caspase-2 activation are unclear. Severe ER stress activates the protease Caspase-2 as an early apoptotic switch upstream of mitochondria. However, if ER stress is irremediable, sustained IRE1α RNase activity triggers cell death.
UPR signaling requires IRE1α, an ER transmembrane kinase-endoribonuclease (RNase) that becomes activated by unfolded protein accumulation within the ER and excises a segment in XBP1 messenger RNA (mRNA) to initiate production of the homeostatic transcription factor XBP1s.
The unfolded protein response (UPR) adjusts the protein folding capacity of the endoplasmic reticulum (ER) to match demand.
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