Endoplasmic reticulum: a focal point of Zika virus infection

Mohd Ropidi, Muhammad Izzuddin; Khazali, Ahmad Suhail; Nor Rashid, Nurshamimi; Yusof, Rohana

Alternatively, IRE1 protein can also mediate ER stressinduced apoptosis following chronic stress damage by triggering activation of apoptotic signaling kinase 1 (ASK1), which consequently activates p38 mitogen-activated protein kinase (p38 MAPK) and Jun N-terminal kinase (JNK) leading to apoptosis [59] . JNK mediates apoptosis primarily by inhibiting the anti-apoptotic B-cell lymphoma 2 (BCL-2) and activating the pro-apoptotic BIM protein [59] , whereas p38 MAPK promotes apoptosis by phosphorylating CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP) at serine residues 78 and 81 to enhance its transcriptional activity and induce apoptosis [60, 61] . CHOP is expressed downstream of all three ER stress sensors, indicating overlapping UPR pathways during severe ER stress [62] . CHOP forms heterodimers with other C/EBP family transcription factors; therefore, the basic domain in CHOP renders the transcription factors incapable of binding to their respective DNA binding sites, which reduces the expression of their target proteins including BCL-2 [63] . CHOP also contains a TAD and thus, can bind to a unique sequence to induce the expression of target genes including BIM [63, 64] .