Figure 5.

Overview of the proposed mechanism of TFEB activation by trehalose. Trehalose is first taken up by endocytic means and accumulates in lysosomes (note: SLC2A8-independent uptake is only demonstrated in macrophages). The rise in intra-lysosomal trehalose concentration results in modest increases in lysosomal pH, which is sufficient to perturb MTORC1 signaling. Reductions in MTOR activity relieves it suppressive effect on TFEB, resulting in its nuclear translocation and induction of the autophagy-lysosomal biogenesis response. In this context, trehalose functions as a TFEB activator via mild perturbation of lysosomal acidity and function