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The unfolded protein response in health and disease
Author(s) -
Walter Peter
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.229.3
Subject(s) - unfolded protein response , endoplasmic reticulum , microbiology and biotechnology , rna splicing , xbp1 , biology , endoribonuclease , protein folding , cytosol , secretory pathway , gene , golgi apparatus , rna , genetics , biochemistry , rnase p , enzyme
Virtually all proteins that eukaryotic cells display on their cell surface or secrete into the extracellular space are folded and assembled in the endoplasmic reticulum (ER). When the protein folding capacity of the ER is exceeded, misfolded proteins accumulate and trigger the unfolded protein response (UPR), an intracellular signaling pathway that reestablishes homeostasis by adjusting ER abundance according to need. The UPR transmits the signal that controls its transcriptional output form the ER lumen to the nucleus. Mechanistic studies have revealed unprecedented ways through which eukaryotic gene expression can be controlled. A key player is Ire1, a bifunctional ER‐resident transmembrane kinase/endoribonuclease, that senses misfolded proteins in the ER lumen and initiates a non‐conventional mRNA splicing reaction in the cytosol. Splicing results in the production of a transcription factor that activates UPR target genes. If proper balance between the load and the protein folding capacity in the ER cannot be established, metazoan cells undergo apoptosis. This role in making life/death decisions places the UPR as a potential player at the center of many diseases, including virus infections, protein diseases, diabetes, and cancer. Our current ideas regarding how Ire1 monitors conditions inside the ER lumen will be discussed.