Loss-of-function diseases are often caused by destabilizing mutations that lead 
to protein misfolding and degradation. Modulating the innate protein homeostasis 
(proteostasis) capacity may lead to rescue of native folding of the mutated 
variants, thereby ameliorating the disease phenotype. In lysosomal storage 
disorders (LSDs), a number of highly prevalent alleles have missense mutations 
that do not impair the enzyme's catalytic activity but destabilize its native 
structure, resulting in the degradation of the misfolded protein. Enhancing the 
cellular folding capacity enables rescuing the native, biologically functional 
structure of these unstable mutated enzymes. However, proteostasis modulators 
specific for the lysosomal system are currently unknown. Here, we investigate 
the role of the transcription factor EB (TFEB), a master regulator of lysosomal 
biogenesis and function, in modulating lysosomal proteostasis in LSDs. We show 
that TFEB activation results in enhanced folding, trafficking and lysosomal 
activity of a severely destabilized glucocerebrosidase (GC) variant associated 
with the development of Gaucher disease (GD), the most common LSD. TFEB 
specifically induces the expression of GC and of key genes involved in folding 
and lysosomal trafficking, thereby enhancing both the pool of mutated enzyme and 
its processing through the secretory pathway. TFEB activation also rescues the 
activity of a β-hexosaminidase mutant associated with the development of another 
LSD, Tay-Sachs disease, thus suggesting general applicability of TFEB-mediated 
proteostasis modulation to rescue destabilizing mutations in LSDs. In summary, 
our findings identify TFEB as a specific regulator of lysosomal proteostasis and 
suggest that TFEB may be used as a therapeutic target to rescue enzyme 
homeostasis in LSDs.