Signaling pathways from the endoplasmic reticulum and their roles in disease

Abstract

The endoplasmic reticulum (ER) is an organelle in which newly synthesized secretory and transmembrane proteins are assembled and folded into their correct tertiary structures. However, many of these ER proteins are misfolded as a result of various stimuli and gene mutations. The accumulation of misfolded proteins disrupts the function of the ER and induces ER stress. Eukaryotic cells possess a highly conserved signaling pathway, termed the unfolded protein response (UPR), to adapt and respond to ER stress conditions, thereby promoting cell survival. However, in the case of prolonged ER stress or UPR malfunction, apoptosis signaling is activated. Dysfunction of the UPR causes numerous conformational diseases, including neurodegenerative disease, metabolic disease, inflammatory disease, diabetes mellitus, cancer, and cardiovascular disease. Thus, ER stress-induced signaling pathways may serve as potent therapeutic targets of ER stress-related diseases. In this review, we will discuss the molecular mechanisms of the UPR and ER stress-induced apoptosis, as well as the possible roles of ER stress in several diseases.

Figure 1

Survival signaling under endoplasmic reticulum (ER) stress conditions. The accumulation of misfolded proteins activates three ER stress sensors: activating transcription factor-6 (ATF6), inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), and double-stranded RNA-dependent protein kinase (PKR)-like eukaryotic initiation factor 2α (eIF2α) kinase (PERK). ATF6 is activated following cleavage with S1P and S2P, after transport to the Golgi. Activated ATF6 (ATF6(N)) functions as a transcription factor and induces the expression of ER chaperones and XBP1. Activated IRE1 induces the splicing of XBP1 messenger RNA (mRNA), and the resulting spliced XBP1 protein (XBP1s) translocates to the nucleus and controls the transcription of ER-resident chaperones and genes involved in lipogenesis and ER-associated degradation (ERAD). The activated PERK subsequently blocks general protein synthesis by phosphorylation of eIF2α, which enables the translation of eIF2α-activating transcription factor-4 (ATF4). ATF4 then translocates to the nucleus and induces the transcription of many genes required for ER quality control.

Figure 2

Apoptosis signaling under ER stress conditions. Prolonged or severe ER stress, as well as dysfunction of the unfolded protein response (UPR), induces apoptosis signaling, primarily through the IRE1 and PERK pathways. In the IRE1 pathway, activated IRE1 recruits TRAF2 and ASK1 on the ER membrane and activates the ASK1-dependent apoptosis pathway. In addition, the IKK-NFκB pathway is also activated by IRE1-TRAF2 and induces an apoptotic response. Proapoptotic Bcl-2 family members, Bax and Bak, interact with IRE1 and promote its RNase/kinase activity. Moreover, IRE1 induces ER-localized mRNA degradation. In the PERK pathway, ATF4 induced by the PERK-eIF2α pathway upregulates the expression of CHOP, which in turn activates the transcription of GADD34, ER oxidoreductase 1 (ERO1), and many proapoptotic factors. GADD34 then promotes dephosphorylation of eIF2α with PP1, canceling translational attenuation, and leads to an increase of protein loads into the ER. Furthermore, the translational attenuation of global proteins by the PERK-eIF2α pathway also applies to IκB, which has been terminally linked to the activation of NFκB.

Figure 3

Mammalian ERAD: the HRD1 complex. ER luminal misfolded proteins are recognized by machinery including ER chaperone BiP, DnaJ family ERdj5, and lectins, such as ER degradation enhancing alpha-mannosidase-like protein (EDEM) family members, OS-9, and XTP3-B. Following its recognition, the terminally misfolded protein is recruited to the HRD1 complex via binding with SEL1L and is then brought to a putative retrotranslocon channel, which may include Derlin family proteins, HRD1, or the Sec61 complex. Finally, the protein is dislocated from the ER to the cytosol. Cytoplasm-exposed substrates are ubiquitinated by E3 ubiquitin ligase HRD1, and extracted by the p97-Npl4-Ufd1 complex anchored on the ER transmembrane through VIMP in an ATP-dependent manner. Finally, the extracted substrate is deglycosylated by PNGase, deubiquitinated, and degraded by the proteasome.