Overview of unfolded protein response (UPR) signalling. (IMAGE)
Caption
The UPR is triggered by three key signal transducers: inositol-requiring enzyme 1 (IRE1) alpha and beta, protein kinase RNA-like ER kinase (PERK) and activating transcription factor-6 (ATF6) alpha and beta. The most evolutionarily conserved branch of the UPR is initiated by the stress sensor IRE1α (termed IRE1 here). This protein, located in the endoplasmic reticulum (ER), functions as both a kinase and an endoribonuclease. On activation, IRE1α splices the mRNA of the transcription factor X-Box-binding protein 1 (XBP1), removing a 26-nucleotide intron. This splicing shifts the reading frame, resulting in the production of XBP1s, a potent transcriptional activator that upregulates various proteostasis effectors. Additionally, IRE1 mediates the direct degradation of certain RNAs via Regulated IRE1-Dependent Decay of RNA (RIDD). PERK acts as a kinase within the integrated stress response, phosphorylating eIF2α to reduce general protein synthesis. However, the phosphorylation of eIF2α selectively increases the translation of ATF4, a transcription factor that regulates genes involved in protein folding, metabolism, and apoptosis. Phosphatases CReP and GADD34 dephosphorylate eIF2α, allowing the resumption of protein translation. Under ER stress, ATF6α, a transmembrane transcription factor, is processed in the Golgi apparatus. This processing releases the cytosolic domain (ATF6f), which then functions as a transcription factor to promote adaptive cellular responses. ERAD, ER-associated degradation.
Credit
By Claudio Hetz, Juan Francisco Silva-Agüero, Lisa M Ellerby
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License
CC BY-NC