TFEB dynamical model reveals a novel feedback loop biological mechanism

Abstract

The transcription factor EB (TFEB) is a key component of the transcriptional regulation of lysosomal biogenesis and autophagy in response to starvation. Autophagy is a self-degradative process activated by cells to survive during nutrient deficiency. In normal conditions, TFEB is sequestered in the cytoplasm through phosphorylation. Following starvation, TFEB is dephosphorylated and translocates into the nucleus binding DNA and promoting the activation of its target genes. Here, we developed a quantitative dynamical model of TFEB regulation to elucidate the biological mechanisms driving its regulation. A two-compartment model (nucleus and cytoplasm) was developed where two different species (de/phosphorylated TFEB) for each compartment are considered. Both de/phosphorylation and transport are modeled as first order kinetics whereas the input (the lack of nutrients) acts by changing the de/phosphorylation rates. Model parameters were identified by fitting experimental data including time-series single cells data acquired via a microfluidics-based platform. The model was able to correctly predict experimental data and was used to hypothesise the existence of a negative feedback loop driving TFEB regulation mediated by autophagy.