Frame switch splicing and regulated intramembrane proteolysis: key words to understand the unfolded protein response.
Proteins must be correctly folded and assembled to fulfill their functions as assigned by genetic code. All living cells have developed systems to counteract protein unfolding or misfolding. A typical example of such a homeostatic response is triggered when unfolded proteins are accumulated in the endoplasmic reticulum. Eukaryotic cells cope with endoplasmic reticulum stress by attenuating translation, generally to decrease the burden on the folding machinery, as well as by inducing transcription of endoplasmic reticulum-localized molecular chaperones and folding enzymes to augment folding capacity. These translational and transcriptional controls are collectively termed the unfolded protein response. The unfolded protein response is unique in that the molecular mechanisms it uses to transmit signals from the endoplasmic reticulum lumen to the nucleus are completely different from those used for signaling from the plasma membrane. Frame switch splicing (a term newly proposed here) and regulated intramembrane proteolysis (proposed by Brown et al., Cell 2000; 100: 391-398) employed by the unfolded protein response represent novel ways to activate a signaling molecule post-transcriptionally and post-translationally, respectively. They are critically involved in various cellular regulation pathways ranging from bacterial extracytoplasmic stress response to differentiation of mature B cells into antibody-secreting plasma cells. Further, mammalian cells take advantage of differential properties between the two mechanisms to determine the fate of proteins unfolded or misfolded in the endoplasmic reticulum. This review focuses on the transcriptional control that occurs during the unfolded protein response in various species.
Mori
Kazutoshi
K
Graduate School of Biostudies, Kyoto University, 46-29 Yoshida-Shimoadachi, Sakyo-ku, Kyoto 606-8304, Japan. kazu.mori@bio.mbox.media.kyoto-u.ac.jp
D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology; D004926:Escherichia coli / Q000502:physiology; D017510:Protein Folding; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology*; D016364:Reading Frames / Q000502:physiology*