IRE1 signaling pathway mediates protective autophagic response against manganese-induced neuronal apoptosis in vivo and in vitro

Abstract Overexposure to manganese (Mn) can result in neurotoxicity and is associated with manganism, a Parkinson's-like neurological disorder. In addition, Mn can induce endoplasmic reticulum (ER) stress and autophagy. In this study, we used C57BL/6 mice to establish a model of manganism and found that Mn could induce cell injury. Our results also showed that Mn could initiate the unfolded protein response (UPR) signaling and autophagy, via initiation of the UPR signaling occurring earlier than autophagy. We further investigated the intrinsic relationship between the endoplasmic reticulum to nucleus 1(ERN1, also known as inositol requiring enzyme 1, IRE1) signaling pathway and autophagy induction in SH-SY5Y cells exposed to Mn. Our results revealed that autophagy activation was a protective response in Mn-induced toxicity. Additionally, we found that Jun N-terminal kinase (JNK) inhibition downregulated autophagy and interaction of c-Jun with the Beclin1 promoter. In addition, knockdown of IRE1 with the LV-IRE1 shRNA suppressed the expression of IRE1, TRAF2, p-ASK1, and p-JNK in Mn-treated SH-SY5Y cells. Furthermore, the expression of proteins associated with ASK1-TRAF2 complex formation and autophagy activation were reversed by the LV-IRE1 shRNA. These findings suggest that IRE1 was involved in the activation of JNK through the formation of the ASK1-TRAF2 complex, and JNK activation led to the induction of autophagy, which required Beclin1 transcription by c-Jun. In this study, we demonstrated that the IRE1 signaling pathway mediated the activation of JNK signaling via the formation of the ASK1-TRAF2 complex which could initiate autophagy and the protein c-Jun which regulates Beclin1 transcription in Mn-induced neurotoxicity.