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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:Methylmercury (MeHg) is a notorious neurotoxin, and its production and degradation in the environment are mainly driven by microorganisms. A variety of microbial MeHg producers carrying the gene pair hgcAB and degraders carrying the merB gene have been separately reported in recent studies. However, surprisingly little attention has been paid to the simultaneous investigation of the diversities of microbial MeHg producers and degraders in a given habitat, and no studies have been performed to explore to what extent these two contrasting microbial groups correlate with MeHg accumulation in the habitat of interest. Here, we collected 86 acid mine drainage (AMD) sediments from an area spanning approximately 500,000 km2 in southern China and profiled the sediment-borne putative MeHg producers and degraders using genome-resolved metagenomics. 46 metagenome-assembled genomes (MAGs) containing hgcAB and 93 MAGs containing merB were obtained, including those from various taxa without previously known MeHg-metabolizing microorganisms. These diverse MeHg-metabolizing MAGs were formed largely via multiple independent horizontal gene transfer (HGT) events. The putative MeHg producers from Deltaproteobacteria and Firmicutes as well as MeHg degraders from Acidithiobacillia were closely correlated with MeHg accumulation in the sediments. Furthermore, these three taxa, in combination with two abiotic factors, explained over 60% of the variance in MeHg accumulation. Most of the members of these taxa were characterized by their metabolic potential for nitrogen fixation and copper tolerance. Overall, these findings improve our understanding of the ecology of MeHg-metabolizing microorganisms and likely have implications for the development of management strategies for the reduction of MeHg accumulation in the AMD sediments. IMPORTANCE Microorganisms are the main drivers of MeHg production and degradation in the environment. However, little attention has been paid to the simultaneous investigation of the diversities of microbial MeHg producers and degraders in a given habitat. We used genome-resolved metagenomics to reveal the vast phylogenetic and metabolic diversities of putative MeHg producers and degraders in AMD sediments. Our results show that the diversity of MeHg-metabolizing microorganisms (particularly MeHg degraders) in AMD sediments is much higher than was previously recognized. Via multiple linear regression analysis, we identified both microbial and abiotic factors affecting MeHg accumulation in AMD sediments. Despite their great diversity, only a few taxa of MeHg-metabolizing microorganisms were closely correlated with MeHg accumulation. This work underscores the importance of using genome-resolved metagenomics to survey MeHg-metabolizing microorganisms and provides a framework for the illumination of the microbial basis of MeHg accumulation via the characterization of physicochemical properties, MeHg-metabolizing microorganisms, and the correlations between them.

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.

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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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