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NLRP3 inflammasome activation is regulated by autophagy, a process tightly controlled by the ATG16L family proteins. However, the inside mechanisms remain elusive. Although the autophagy-related protein ATG16L1 has been well characterized, regulation and biological functions of its close homolog ATG16L2 still remain elusive. Here we report that ATG16L2 deficiency attenuates LPS-induced autophagy flux in macrophages through mediating ATG5-12-16L1 complex assembly. Importantly, NLRP3 inflammasome activation is elevated in ATG16L2-deficient macrophages, which also have defects in mitochondrial integrity and respiration. Finally, ATG16l2 knockout mice are more susceptible to DSS-induced intestinal damage, which can be ameliorated by inhibition of NLRP3. Collectively, our data demonstrate that ATG16L2 positively regulates autophagy and ATG16L2 could be a potential target for manipulating aberrant NLRP3 inflammasome activation induced inflammatory diseases.

Microcystin-leucine-arginine (MC-LR) is a toxin secreted by freshwater cyanobacteria that is considered a potential environmental risk factor for Alzheimer's disease (AD). A previous study indicated that tau protein hyperphosphorylation via protein phosphatase 2A (PP2A) and GSK-3β inhibition was the mechanism by which MC-LR induces neurotoxicity; however, how MC-LR-induced neurotoxicity can be effectively prevented remains unclear. In this study, the reversal effect of metformin on MC-LR-induced neurotoxicity was investigated. The results showed that metformin effectively prevented tau hyperphosphorylation at Ser202 caused by MC-LR through PP2A and GSK-3b activity. The effect of metformin on PP2A activity was dependent on the inhibition of mTOR in MC-LR-treated SH-SY5Y cells. Metformin prevented spatial memory deficits in rats caused by intrahippocampal MC-LR administration. In sum, the results suggested that metformin can ameliorate the MC-LR-induced AD-like phenotype by preventing tau phosphorylation at Ser202, which was mainly mediated by mTOR-dependent PP2A and GSK-3β activation.

Microcystin-leucine-arginine (MC-LR) is a toxin secreted by freshwater cyanobacteria that is considered a potential environmental risk factor for Alzheimer's disease (AD). A previous study indicated that tau protein hyperphosphorylation via protein phosphatase 2A (PP2A) and GSK-3β inhibition was the mechanism by which MC-LR induces neurotoxicity; however, how MC-LR-induced neurotoxicity can be effectively prevented remains unclear. In this study, the reversal effect of metformin on MC-LR-induced neurotoxicity was investigated. The results showed that metformin effectively prevented tau hyperphosphorylation at Ser202 caused by MC-LR through PP2A and GSK-3b activity. The effect of metformin on PP2A activity was dependent on the inhibition of mTOR in MC-LR-treated SH-SY5Y cells. Metformin prevented spatial memory deficits in rats caused by intrahippocampal MC-LR administration. In sum, the results suggested that metformin can ameliorate the MC-LR-induced AD-like phenotype by preventing tau phosphorylation at Ser202, which was mainly mediated by mTOR-dependent PP2A and GSK-3β activation.

Microcystin-LR (MC-LR), the most common and toxic microcystin (MC) present in freshwater, poses a substantial threat to human health, especially hepatotoxicity. Recent evidence reveals that the NLRP3 inflammasome plays an important role in liver injury by activating caspase-1 to promote interleukin-1β (IL-1β) secretion. In this study, we investigated the possible role of NLRP3 inflammasome activation in MC-LR-induced mouse liver inflammatory injury. We found that MC-LR administered to mice by oral gavage mainly accumulated in liver and induced the activation of the NLRP3 inflammasome and production of mature IL-1β. Additionally, we observed an increase in the levels of NLRP3 inflammasome-related proteins and the proportion of pyroptosis in MC-LR-treated AML-12 cells. We also found that inhibition of NLRP3 in mice attenuated MC-LR-induced IL-1β production, indicating an essential role for NLRP3 in MC-LR-induced liver inflammatory injury. In addition, we found that inhibition of FOXO1 by AKT-mediated hyperphosphorylation, due to protein phosphatase 2A (PP2A) inhibition, is required for MC-LR-induced expression of NLRP3. Taken together, our in vivo and in vitro findings suggest a model in which the NLRP3 inflammasome activation, a result of AKT-mediated hyperphosphorylation of FOXO1 through inhibition of PP2A, plays a key role in MC-LR–induced liver inflammatory injury via IL-1β secretion and pyroptotic cell death.

Microcystin-leucine-arginine (MC-LR) has been implicated as a potential environmental factor in Alzheimer's disease because of its potent inhibition of protein phosphatase 2A (PP2A) activity, but experimental evidence to support its detailed neurotoxic effects and their underlying mechanisms has been lacking. The present study investigated the role of PP2A catalytic subunit (PP2Ac) demethylation and its link with glycogen synthase kinase-3β (GSK)-3β in tau hyperphosphorylation induced by MC-LR. The results showed that MC-LR treatment significantly increased demethylation of PP2Ac, with a concomitant increase in GSK-3β phosphorylation at Ser9 resulting in elevated tau hyperphosphorylation at PP2A-favorable sites in SH-SY5Y cells and rat hippocampus. Coimmunoprecipitation experiments showed that MC-LR treatment dissociated PP2Ac from Bα, making it incompetent in binding tau, thus causing tau hyperphosphorylation. Moreover, we found that inhibition of PP2A resulted in an increase in phosphorylation of GSK-3β at Ser9 and a decrease in GSK-3β activity, which further promoted demethylation of PP2Ac induced by MC-LR. These findings suggest a scenario in which MC-LR-mediated demethylation of PP2Ac is associated with GSK-3β phosphorylation at Ser9 and contributes to dissociation of Bα from PP2Ac, which would result in Bα degradation and disruption of PP2A/Bα-tau interactions, thus promoting tau hyperphosphorylation and paired helical filaments-tau accumulation and, consequently, axonal degeneration and cell death.