Autophagy, including macroautophagy, microautophagy, and chaperone-mediated autophagy,plays critical roles in recycling of damaged organelle and misfolded protein, and senses nutrient starvation and infection.Autophagy functions as an adaptive response to stress stimuli to protect cells against cell death, and dysfuntional autophagy leads to morbidity, developmental abnormalities, and cell death.In mammalian cells, the regulation of autophagy by amino acid or insulin has been well studied, however, how glucose modulates autophagy is still limited.Glucose acts as a critical effector in some human diseases, such as diabetes and cancer,therefore dissecting the mechanism of how glucose regulates autophagy not only helps better understanding autophagy but also provides a potential therapeutic strategy for the glucose related human diseases.A complex of signaling networks, including inhibitory and stimulatory components, participate in regulating mammalian autophagy.Nutrients normally activate the Ras-Raf-MEK-ERK pathway to suppress autophagy.Interestingly, here we found that in HEK293 cells glucose deprivation transiently activated ERK1/2, which peaked around 5 to 10 min, thereafter returned to basal.Prolonged glucose deprivation markedly induced autophagy in HEK293 cells, as reflected by dramatically increased LC3-Ⅱ accumulation and LC3 puncta.U0126, a specific inhibitor of ERKs, inhibit glucose deprivation-induced autophagy by inactivation of ERKs.Similarly, expressing constitutively activate ERK2 activated autophagy in HEK293 cells, whereas double knockdown B-Raf/C-Raf and expression of dominant negative mutant of either MEKs, or HRas, or ERK2 blocked glucose starvation-induced autophagy.Interestingly, we find that glucose starvation-induced autophagy through ERKs activation is cell type specific which is only in renal cells.We also confirmed that glucose starvation can stimulate reactive oxygen species (ROS) generation which can be blocked by NAC, a ROS inhibitor.What's more, N-Acetyl-l-cysteine (NAC) can inhibit glucose starvation-induced autophagy by ERKs inactivation.We are currently investigating how glucose deprivation induced ROS to activate MAPK signaling pathway in mammalian cells, what is/are the downstream effector(s)of ERKs to initiate autophagy, and the physiological role of ERKs-activated autophagy in gluconeogenesis of renal tubule cells.