Autophagy, the starvation-induced degradation of bulky cytosolic components, is up-regulated in mammalian cells when nutrient supplies are limited. Although mammalian target of rapamycin (mTOR) is known as the key regulator of autophagy induction, the mechanism by which mTOR regulates autophagy has remained elusive. Here, we identify that mTOR phosphorylates a mammalian homologue of Atg13 and the mammalian Atg1 homologues ULK1 and ULK2. The mammalian Atg13 binds both ULK1 and ULK2 and mediates the interaction of the ULK proteins with FIP200. The binding of Atg13 stabilizes and activates ULK and facilitates the phosphorylation of FIP200 by ULK, whereas knockdown of Atg13 inhibits autophagosome formation. Inhibition of mTOR by rapamycin or leucine deprivation, the conditions that induce autophagy, leads to dephosphorylation of ULK1, ULK2, and Atg13 and activates ULK to phosphorylate FIP200. These findings demonstrate that the ULK-Atg13-FIP200 complexes are direct targets of mTOR and important regulators of autophagy in response to mTOR signaling.

a b s t r a c tNutrient starvation induces autophagy in eukaryotic cells through inhibition of TOR (target of rapamycin), an evolutionarily-conserved protein kinase. TOR, as a central regulator of cell growth, plays a key role at the interface of the pathways that coordinately regulate the balance between cell growth and autophagy in response to nutritional status, growth factor and stress signals. Although TOR has been known as a key regulator of autophagy for more than a decade, the underlying regulatory mechanisms have not been clearly understood. This review discusses the recent advances in understanding of the mechanism by which TOR regulates autophagy with focus on mammalian TOR (mTOR) and its regulation of the autophagy machinery.

In recent years, the study of oxidative stress (OS) has become increasingly popular. In particular, the role of OS on female fertility is very important and has been focused on closely. The occurrence of OS is due to the excessive production of reactive oxygen species (ROS). ROS are a double-edged sword; they not only play an important role as secondary messengers in many intracellular signaling cascades, but they also exert indispensable effects on pathological processes involving the female genital tract. ROS and antioxidants join in the regulation of reproductive processes in both animals and humans. Imbalances between pro-oxidants and antioxidants could lead to a number of female reproductive diseases. This review focuses on the mechanism of OS and a series of female reproductive processes, explaining the role of OS in female reproduction and female reproductive diseases caused by OS, including polycystic ovary syndrome (PCOS), endometriosis, preeclampsia and so on. Many signaling pathways involved in female reproduction, including the Keap1-Nrf2, NF-κB, FOXO and MAPK pathways, which are affected by OS, are described, providing new ideas for the mechanism of reproductive diseases.

Intestinal diseases caused by sleep deprivation (SD) are severe public health threats worldwide. This study focuses on the effect of melatonin on intestinal mucosal injury and microbiota dysbiosis in sleep‐deprived mice. Mice subjected to SD had significantly elevated norepinephrine levels and decreased melatonin content in plasma. Consistent with the decrease in melatonin levels, we observed a decrease of antioxidant ability, down‐regulation of anti‐inflammatory cytokines and up‐regulation of pro‐inflammatory cytokines in sleep‐deprived mice, which resulted in colonic mucosal injury, including a reduced number of goblet cells, proliferating cell nuclear antigen‐positive cells, expression of MUC2 and tight junction proteins and elevated expression of ATG5, Beclin1, p‐P65 and p‐IκB. High‐throughput pyrosequencing of 16S rRNA demonstrated that the diversity and richness of the colonic microbiota were decreased in sleep‐deprived mice, especially in probiotics, including Akkermansia, Bacteroides and Faecalibacterium. However, the pathogen Aeromonas was markedly increased. By contrast, supplementation with 20 and 40 mg/kg melatonin reversed these SD‐induced changes and improved the mucosal injury and dysbiosis of the microbiota in the colon. Our results suggest that the effect of SD on intestinal barrier dysfunction might be an outcome of melatonin suppression rather than a loss of sleep per se. SD‐induced intestinal barrier dysfunction involved the suppression of melatonin production and activation of the NF‐κB pathway by oxidative stress.

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