The study investigates the role of transcription factor EB (TFEB) in linking autophagy to lysosomal biogenesis during starvation. TFEB, a key regulator of lysosomal biogenesis, is found to coordinate the autophagic pathway by controlling the expression of autophagy and lysosomal genes. Nuclear localization and activity of TFEB are regulated by serine phosphorylation mediated by extracellular signal-regulated kinase 2 (ERK2), which is influenced by extracellular nutrient levels. Overexpression of TFEB in HeLa cells increases the number of autophagosomes and enhances autophagic flux, while TFEB knockdown reduces these processes. TFEB's activity is also regulated by MAPK signaling, with ERK2-mediated phosphorylation of TFEB at serine 142 being crucial for its nuclear translocation and activation. In vivo studies in GFP-LC3 transgenic mice show that TFEB is involved in the transcriptional regulation of starvation-induced autophagy. This work identifies a novel transcriptional mechanism that controls multiple steps of the autophagic pathway, suggesting potential therapeutic approaches for modulating cellular clearance.The study investigates the role of transcription factor EB (TFEB) in linking autophagy to lysosomal biogenesis during starvation. TFEB, a key regulator of lysosomal biogenesis, is found to coordinate the autophagic pathway by controlling the expression of autophagy and lysosomal genes. Nuclear localization and activity of TFEB are regulated by serine phosphorylation mediated by extracellular signal-regulated kinase 2 (ERK2), which is influenced by extracellular nutrient levels. Overexpression of TFEB in HeLa cells increases the number of autophagosomes and enhances autophagic flux, while TFEB knockdown reduces these processes. TFEB's activity is also regulated by MAPK signaling, with ERK2-mediated phosphorylation of TFEB at serine 142 being crucial for its nuclear translocation and activation. In vivo studies in GFP-LC3 transgenic mice show that TFEB is involved in the transcriptional regulation of starvation-induced autophagy. This work identifies a novel transcriptional mechanism that controls multiple steps of the autophagic pathway, suggesting potential therapeutic approaches for modulating cellular clearance.