Cell Biology

An Unfolding Story

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Science  14 Jan 2000:
Vol. 287, Issue 5451, pp. 193
DOI: 10.1126/science.287.5451.193a

The unfolded protein response (UPR) is an intracellular signaling pathway that regulates protein folding. Through this pathway, the cell senses when unfolded proteins accumulate in the endoplasmic reticulum (ER) and responds by activating transcription of genes encoding proteins involved in folding, such as chaperones. A key player in this pathway is Ire1p, an ER transmembrane protein with endonuclease and kinase activities. Upon induction of the UPR, Ire1p translocates from the ER to the nucleus, where it initiates the splicing of a messenger RNA specifying a transcription factor that activates UPR target genes.

The mechanism of translocation has now been clarified by Niwa et al., who show that Ire1p is proteolytically severed from the ER membrane, producing a soluble, enzymatically active fragment which then enters the nucleus. In an intriguing twist to this story, both Niwa et al. and Katayama et al. show that nuclear localization of Ire1p and UPR induction are impaired in cells lacking or defective in presenilin-1, a protease linked to the aberrant production of amyloid deposits in Alzheimer's disease (AD), suggesting that defects in UPR may play a role in the pathogenesis of AD.—PAK

Cell99, 691 (1999); Nature Cell Biol.1, 479 (1999).

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