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MeHg-induced autophagy via JNK/Vps34 complex pathway promotes autophagosome accumulation and neuronal cell death.

ABSTRACT: Methylmercury (MeHg), an environmental toxin, may specifically cause neurological disorders. Recent studies have reported that autophagy can be induced by metals and be involved in metal cytotoxicity. However, the role of autophagy in MeHg-induced neurotoxicity remains unknown. Here, we demonstrate that MeHg induces mTOR-independent autophagy through JNK/Vps34 complex pathway, which further promotes autophagosome accumulation and neuronal cell death. In addition to cell death, MeHg increased LC3-II expression in a concentration- and time-dependent manner in neuronal cells; furthermore, western blot analysis of LC3-II expression under baf A1-treated condition indicates that MeHg activates autophagy induction. However, we found lysosomal degradative function was impaired by MeHg. Under this condition, MeHg-activated autophagy induction would elicit autophagosome accumulation and cell death. Consistent with this inference, the autophagy inhibitor decreased the MeHg-induced autophagosome accumulation and neuronal cells death, whereas the autophagy inducers further augmented MeHg cytotoxicity. Then, the mechanism of autophagy induction is investigated. We show that MeHg-induced autophagy is mTOR-independent. Vacuolar protein sorting 34 (Vps34) complex is critical for mTOR-independent autophagy. MeHg induced the interaction between Beclin1 and Vps34 to form Vps34 complex. Importantly, knockdown of Vps34 inhibited autophagy induction by MeHg. Furthermore, we found that JNK, but not p38 or ERK, promoted the formation of Vps34 complex and autophagy induction. Finally, inhibition of JNK or downregulation of Vps34 decreased autophagosome accumulation and alleviated MeHg-induced neuronal cell death. The present study implies that inhibiting JNK/Vps34 complex autophagy induction pathway may be a novel therapeutic approach for the treatment of MeHg-induced neurotoxicity.

SUBMITTER: Lin T

PROVIDER: S-EPMC6529499 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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MeHg-induced autophagy via JNK/Vps34 complex pathway promotes autophagosome accumulation and neuronal cell death.

Lin Tianji T Ruan Shijuan S Huang Dingbang D Meng Xiaojing X Li Wenjun W Wang Bin B Zou Fei F

Cell death & disease 20190521 6

Methylmercury (MeHg), an environmental toxin, may specifically cause neurological disorders. Recent studies have reported that autophagy can be induced by metals and be involved in metal cytotoxicity. However, the role of autophagy in MeHg-induced neurotoxicity remains unknown. Here, we demonstrate that MeHg induces mTOR-independent autophagy through JNK/Vps34 complex pathway, which further promotes autophagosome accumulation and neuronal cell death. In addition to cell death, MeHg increased LC3 ...[more]

PMID: 31113939

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Project description:Autophagy is a lysosome-dependent degradation program to maintain cellular homeostasis in response to a variety of stressful conditions, such as long-lived or non-functional subcellular organelles, protein aggregates, nutrient limitation, and virus/bacteria infection. Accordingly, dysregulation of autophagy is closely associated with many human pathophysiological conditions, such as neurodegenerative diseases, aging, and cancer, and autophagy is highlighted as an important therapeutic target for these human diseases. In autophagy process, PIK3C3/VPS34 complex plays important roles in autophagosome biogenesis. Accumulating evidences that inhibition of PIK3C3/VPS34 complex successfully blocks autophagy make the complex as an attractive target for the development of autophagy-specific inhibitors. However, considering that various forms of PIK3C3/VPS34 complex exist and they are involved in many different cellular functions, the targeting of the pro-autophagy PIK3C3/VPS34 complex is required to specifically inhibit autophagy. To identify autophagy inhibitors targeting the pro-autophagy complex, we have performed the screening of a customized natural product library consisting of 35 herbal extracts which are widely used in the oriental medicine as anti-inflammation and/or anti-tumor reagents. We discovered that an alcoholic extract of Thuja orientalis L. leaves inhibits pro-autophagy complex formation by disrupting the interaction between autophagy-specific factor, ATG14L, and the complex core unit Vps34-Beclin 1 in vitro. Also, it inhibits the nutrient starvation induced autophagy and diminished pro-autophagy PIK3C3/VPS34 complex containing either ATG14L or UVRAG in several cell lines. Our results strongly suggest that Thuja orientalis L. leave extract functions as an autophagy-specific inhibitor not decreasing the complex activity nor the protein level, but preventing protein-protein interaction between autophagy-specific factor (ATG14L and UVRAG) and PIK3C3/VPS34 complex core unit, Vps34-Beclin 1, thereby specifically depleting the pro-autophagy complex to inhibit autophagy.

Dataset Information

MeHg-induced autophagy via JNK/Vps34 complex pathway promotes autophagosome accumulation and neuronal cell death.

Publications

MeHg-induced autophagy via JNK/Vps34 complex pathway promotes autophagosome accumulation and neuronal cell death.

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