RRC ID 57236
Author Zhu M, Zhang S, Tian X, Wu C.
Title Mask mitigates MAPT- and FUS-induced degeneration by enhancing autophagy through lysosomal acidification.
Journal Autophagy
Abstract Accumulation of intracellular misfolded or damaged proteins is associated with both normal aging and late-onset degenerative diseases. Two cellular clearance mechanisms, the ubiquitin-proteasome system (UPS) and the macroautophagy/autophagy-lysosomal pathway, work in concert to degrade harmful protein aggregates and maintain protein homeostasis. Here we show that Mask, an Ankyrin-repeat and KH-domain containing protein, plays a key role in promoting autophagy flux and mitigating degeneration caused by protein aggregation or impaired UPS function. In Drosophila eye models of human tauopathy or amyotrophic lateral sclerosis diseases, loss of Mask function enhanced, while gain of Mask function mitigated, eye degenerations induced by eye-specific expression of human pathogenic MAPT/TAU or FUS proteins. The fly larval muscle, a more accessible tissue, was then used to study the underlying molecular mechanisms in vivo. We found that Mask modulates the global abundance of K48- and K63-ubiquitinated proteins by regulating autophagy-lysosome-mediated degradation, but not UPS function. Indeed, upregulation of Mask compensated the partial loss of UPS function. We further demonstrate that Mask promotes autophagic flux by enhancing lysosomal function, and that Mask is necessary and sufficient for promoting the expression levels of the proton-pumping vacuolar (V)-type ATPases in a TFEB-independent manner. Moreover, the beneficial effects conferred by Mask expression on the UPS dysfunction and neurodegenerative models depend on intact autophagy-lysosomal pathway. Our findings highlight the importance of lysosome acidification in cellular surveillance mechanisms and establish a model for exploring strategies to mitigate neurodegeneration by boosting lysosomal function.
Volume 13(11)
Pages 1924-1938
Published 2017-9-18
DOI 10.1080/15548627.2017.1362524
PMID 28806139
PMC PMC5788473
MeSH Amyotrophic Lateral Sclerosis / metabolism* Animals Animals, Genetically Modified Autophagy* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Disease Models, Animal Drosophila Drosophila Proteins / genetics Drosophila Proteins / metabolism* Humans Lysosomes / metabolism* RNA-Binding Protein FUS / genetics RNA-Binding Protein FUS / metabolism* Tauopathies / metabolism* Ubiquitination* Vacuolar Proton-Translocating ATPases / metabolism tau Proteins / genetics tau Proteins / metabolism*
IF 11.059
Times Cited 4