Significant progress has been made in identifying components of the UPR pathways and in understanding physiological roles of the UPR. However, our knowledge of the UPR pathway is still incomplete. There remains much to do in identifying new substrates for the known UPR transducers and new transducers for unknown UPR pathways. Furthermore, it will be extremely important to elucidate the sensing mechanisms for the UPR transducers under different physiological conditions. Studies of this most upstream event in the UPR promise to expand our understanding of the UPR signaling pathway itself and its physiological functions. It is known that a variety of environmental insults and genetic diseases result in accumulation of unfolded or misfolded proteins in the ER that contribute to the pathogenesis of different disease states. As new animal models with defects in different signaling components of the UPR are generated, a more precise knowledge of the extent to which these pathways cause or arise as a consequence of different pathological conditions will be gained. Elucidating which components of the UPR are beneficial versus those that are detrimental under different conditions of stress represents a major avenue of research for the future. As we gain a greater understanding of the mechanisms and physiological roles of the UPR, it should be possible to design novel therapies for the diseases associated with abnormal accumulation of unfolded or misfolded proteins by activating or inhibiting the UPR signaling as desired.
* This minireview will be reprinted in the 2004 Minireview Compendium, which will be available in January, 2005. This work was supported by National Institutes of Health Grant DK42394 (to R. J. K.).
¶ To whom correspondence should be addressed: Howard Hughes Medical Institute, Dept. of Biological Chemistry, 1150 W. Medical Center Dr., University of Michigan Medical Center, Ann Arbor, MI 48109. Tel.: 734-763-9037; Fax: 734-763-9323; E-mail: [email protected]
1 The abbreviations used are: ER, endoplasmic reticulum; UPR, unfolded protein response; IRE, inositol-requiring enzyme; ATF, activating transcription factor; PERK, double-stranded RNA-activated protein kinase-like ER kinase; XBP, X-box-binding protein; UPRE, unfolded protein response element; ERSE, ER stress response element; eIF, eukaryotic initiation factor; b-ZIP, basic leucine zipper; ERAD, ER-associated degradation; GRP, glucose-regulated protein.
We thank D. T. Rutkowski for comments on this review.