UPR, autophagy, and mitochondria crosstalk underlies the ER stress response

Abstract

Cellular stress, induced by external or internal cues, activates several well-orchestrated processes aimed at either restoring cellular homeostasis or committing to cell death. Those processes include the unfolded protein response (UPR), autophagy, hypoxia, and mitochondrial function, which are part of the global endoplasmic reticulum (ER) stress (ERS) response. When one of the ERS elements is impaired, as often occurs under pathological conditions, overall cellular homeostasis may be perturbed. Further, activation of the UPR could trigger changes in mitochondrial function or autophagy, which could modulate the UPR, exemplifying crosstalk processes. Among the numerous factors that control the magnitude or duration of these processes are ubiquitin ligases, which govern overall cellular stress outcomes. Here we summarize crosstalk among the fundamental processes governing ERS responses.

Keywords: ER stress; UPR; autophagy; hypoxia; mitochondria; ubiquitin.

Figure I. Molecular mechanisms of UPR signaling

The three ERS sensors PERK, ATF6 and IRE1 activate a complex transcriptional cascade with distinct cytosolic functions. PERK phosphorylates eIF2α to decrease overall translation while increasing specific translation of genes, including ATF4. Upon ERS, ATF6 is translocated to and is processed at the golgi apparatus to create a highly active transcription factor. IRE1 decreases overall protein flux to the ER by enhancing mRNA degradation, activates other cellular pathways (such as JNK or NFκB) to counteract ERS and leads to the activation of the XBP1 transcription factor by splicing the uXBP1 mRNA to create sXBP1 mRNA, which is more efficiently translated. All three transcription factors lead to the upregulation of chaperones, in addition to their respective specific targets (indicated in figure) to counteract ERS and restore homeostasis, or proceed to induce cell death pathways. ATF: activating transcription factor; eIF2α: eukaryotic translation initiation factor 2 alpha; IRE1: inositol-requiring enzyme 1; JNK: c-Jun N-terminal kinase; NFκB: Nuclear Factor κB; PERK: double-stranded RNA-activated protein kinase (PKR)-like ER kinase; u/sXBP1: unspliced/spliced x-box binding protein 1.

Figure 1. UPR crosstalk with autophagy

Autophagy is initiated by encapsulation of cytoplasmic components (proteins and organelles) within isolation membranes to form autophagosomes. These structures eventually fuse with lysosomes, and the cargo is degraded. Activation of the PERK–eIF2α–ATF4 pathway upregulates expression of a large set of autophagy genes. While IRE1 signaling has been implicated in promoting autophagy (via JNK-mediated signaling), it was also shown to elicit negative regulation of autophagy. Functionally, autophagy promotes cell survival, increases energy supply and mediates innate immune responses. Loss of autophagy genes induces the UPR, indicative of a negative feedback mechanism. Autophagy may decrease cellular stress levels by removal of ER membranes, which contain UPR sensors, or decrease the amplitude of stress by clearing aberrant proteins from the ER. ATF: activating transcription factor; ATG: autophagy-related gene; Becn1: Beclin 1; eIF2α: eukaryotic translation initiation factor 2; IRE1: inositol-requiring enzyme 1; JNK: c-Jun N-terminal kinase; NF-κB: Nuclear Factor kappa B; PERK: double-stranded RNA-activated protein kinase (PKR)-like ER kinase; UPR: unfolded protein response; u/sXBP1: unspliced/spliced x-box binding protein 1.