ER stress-induced signaling pathways that mediate autophagy

ER stress-induced signaling pathways that mediate autophagy. During induction of autophagy, the ubiquitin-like modification complexes of ATG12 and ATG8 (LC3) play critical roles in the dynamic changes in membranes that coalesce to form autophagosomes. These two ubiquitin-like proteins are targeted to the membrane through interaction with ATG5 and ATG16, or lipidation with phosphatidyle-thanolamine (PE), respectively. The ATG5—ATG12-ATG16 complex promotes conversion of LC3-I (cytosolic soluble form) to LC3-II (membranous lipidated form). In response to ER stress, PERK-mediated phosphorylation of eIF2α induces transcription of ATG12.5 In addition, ER stress-induced activation of the IRE1-JNK pathway is required for recruitment of LC3-II to the autophagosome. Our results show that PKCθ activation is also critical for ER stress-induced autophagy. ER stress induces Ca2+ release from the ER that is required to increase PKCθ phosphorylation. The phosphorylated form of PKCθ is targeted to LC3-II-containing punctate membranes in the cytosol. As PKCθ is a member of the novel PKC family, it is unlikely that Ca2+ directly activates PKCθ. It is also proposed that Ca2+ release from the ER stimulates a CaMKK/AMPK-dependent pathway that inhibits mTORC1 to induce autophagy.

Publication

Regulation of ER stress-induced macroautophagy by protein kinase C. () Kenjiro Sakaki, et al. Autophagy. ;4(6):841-843. Figure: F1. All organisms Homo sapiens Mus musculus Drosophila melanogaster

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