ER Stress Activates the NLRP3 Inflammasome: A Novel Mechanism of Atherosclerosis

Figure 1

UPR signaling pathways. UPR induced by ER stress triggers downstream signaling through three major sensing proteins (IRE1, PERK, and ATF6). (a) IRE1 autophosphorylation induces XBP1-specific cleavage, enhancing ER folding function and UPR gene transcription. Furthermore, activated IRE1 recruits TRAF2 which induces apoptosis and inflammation through JNK and NF-κB pathways. IRE1α also degrades select mRNAs through RIDD. (b) Activated PERK phosphorylates eIF2α which upregulates ATF4 expression to promote UPR gene transcription while inducing NF-κB-mediated inflammatory responses. (c) ATF6 interacts with COPII to transport ATF6 to the Golgi for cleavage, and the resulting ATF6f induces the transcription of downstream genes such as XBP1 and CHOP. UPR: unfolded protein response; ER: endoplasmic reticulum; IRE1: inositol-requiring enzyme 1; PERK: protein kinase RNA- (PKR-) like kinase; ATF6: activating transcription factor 6; XBP1: X-box-binding protein-1; TRAF2: tumour necrosis factor receptor- (TNFR-) associated factor-2; JNK: Jun-N-terminal kinase; NF-κB: nuclear factor κB; RIDD: regulated IRE1-dependent decay; eIF2α: eukaryotic translation initiation factor 2α; ATF4: activating transcription factor 4; COPII: coat protein II; CHOP: CCAAT/enhancer-binding protein-homologous protein.

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