Unfolded protein response (UPR) integrated signaling networks determine cell fate during hypoxia

Abstract

During hypoxic conditions, cells undergo critical adaptive responses that include the up-regulation of hypoxia-inducible proteins (HIFs) and the induction of the unfolded protein response (UPR). While their induced signaling pathways have many distinct targets, there are some important connections as well. Despite the extensive studies on both of these signaling pathways, the exact mechanisms involved that determine survival versus apoptosis remain largely unexplained and therefore beyond therapeutic control. Here we discuss the complex relationship between the HIF and UPR signaling pathways and the importance of understanding how these pathways differ between normal and cancer cell models.

Keywords: Angiogenesis; Cell fate determination; ER-stress; Hypoxia-reoxygenation injury; Ischemia; UPRmt.

Fig. 1

Oxygen availability regulates HIF signaling. In normoxia, proline (P) residues on HIFα subunits are hydroxylated by PHDs that marks them for proteasomal degradation. Additionally, FIH-1 mediates hydroxylation of asparagine residues (N) on HIFα to prevent HIF transcriptional activity. Hypoxia impairs the ability of PHDs and FIH-1 to hydroxylate the HIFα subunits, and thus results in the accumulation of this subunit and its heterodimerization with the stable HIFβ subunits. In the nucleus, the HIFα/β complex binds to HRE elements in the HIF target genes and governs their expression in order to adapt the cells to hypoxic conditions

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

Fig. 3

Hypoxia signaling and the related changes in cellular functions activate the UPR and UPRmt. During hypoxia, accumulation of misfolded/unfolded proteins in ER and mitochondria activate PERK signaling, and this contributes to both pro-survival (global translational arrest and induction of pro-angiogenic genes IL8 and VEGF) and apoptotic responses (induction of CHOP and inhibition of pro-angiogenic eNOS expression). Furthermore, in some models, hypoxia-related activation of ATF6 and IRE1α contributes to pro-survival and pro-angiogenic signaling. There also appears to be cooperation between XBP1s and HIF1 in pro-survival signaling