Fig. 2

UPR and UPRmt signaling. Upon buildup of misfolded/unfolded proteins in ER, BIP is released from ER membrane to induce PERK dimerization and its subsequent autophosphorylation. Activated PERK phosphorylates the eIF2α, leading to global translation attenuation. Some transcripts, however, including ATF4 remain preferably translated. ATF4 provides the transcriptional signal to restore ER homeostasis, however, it can also induce proapoptotic CHOP. Similarly, accumulation of unfolded proteins in mitochondria leads to PERK activation and the induction of ATF4 signaling (UPRmt). Upon its dissociation from BIP, IRE1α undergoes oligomerization and autophosphorylation and thus gains endoribonuclease activity. To decrease the ER load, activated IRE1α degrades mRNAs and miRNAs (RIDD). IRE1α also performs splicing of XBP1 mRNA to release transcriptionally active XBP1s. XBP1s activates a transcriptional program to restore ER homeostasis. Alternatively, IRE1α can activate a proapoptotic kinase JNK1. Finally, BIP dissociation allows ATF6 translocation to Golgi, where cleavage of this protein results in release of transcriptionally active ATF6f. ATF6f activates a transcriptional program to restore ER homeostasis and support ERAD