Figure 3

Mechanisms of ERS-mediated autophagy in animal virus infections. Some animal viruses induce ERS to regulate the activation of autophagy through three UPR signalling pathways: ATF6(N) is formed after ATF6 cleavage, ATF6(N) induces autophagosome formation through CHOP, or by directly regulating ATG5 transcription, or by negatively regulating the AKT-mTOR pathway, or by activating the DAPK1-Beclin1 pathway. The activated IRE1 forms complexes with TRAF2 and ASK1, activating the JNK downstream pathway and then causing Bcl-2 phosphorylation, thereby releasing free Beclin1. In addition, XBP1 also triggers transcriptional activation of Beclin1, resulting in the formation of the Vsp15-Vps34-Beclin1-ATG14 complex to promote vesicle nucleation. Activated PERK regulates the transcription of ATG12 and ATG16 through ATF4, which activates CHOP to induce transcription of ATG5. The formation of the ATG5-ATG12-ATG16 complex engages in the process of autophagosome elongation. Additionally, the ERS state induces Ca²⁺ imbalance, and Ca²⁺ release from the ER lumen via IP3R activates the CaMK-AMPK-mTOR pathway, which promotes the formation of the ULK1 complex to trigger autophagy. Ca²⁺ release also activates DAPK1 to promote Beclin-1 phosphorylation, thus promoting autophagy. Black and blue pointed arrows denote activation, and black and blue blunt-end arrows denote inhibition.