RRC ID 57132
Author Şentürk M, Lin G, Zuo Z, Mao D, Watson E, Mikos AG, Bellen HJ.
Title Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification.
Journal Nat Cell Biol
Abstract Although the aetiology of amyotrophic lateral sclerosis (ALS) remains poorly understood, impaired proteostasis is a common feature of different forms of ALS. Mutations in genes encoding ubiquilins, UBQLN2 and UBQLN4, cause familial ALS. The role of ubiquilins in proteasomal degradation is well established, but their role in autophagy-lysosomal clearance is poorly defined. Here, we describe a crosstalk between endoplasmic reticulum stress, mTOR signalling and autophagic flux in Drosophila and mammalian cells lacking ubiquilins. We found that loss of ubiquilins leads to endoplasmic reticulum stress, impairs mTORC1 activity, promotes autophagy and causes the demise of neurons. We show that ubiquilin mutants display defective autophagic flux due to reduced lysosome acidification. Ubiquilins are required to maintain proper levels of the V0a/V100 subunit of the vacuolar H+-ATPase and lysosomal pH. Feeding flies acidic nanoparticles alleviates defective autophagic flux in ubiquilin mutants. Hence, our studies reveal a conserved role for ubiquilins as regulators of autophagy by controlling vacuolar H+-ATPase activity and mTOR signalling.
Volume 21(3)
Pages 384-396
Published 2019-3-1
DOI 10.1038/s41556-019-0281-x
PII 10.1038/s41556-019-0281-x
PMID 30804504
PMC PMC6534127
MeSH Amyotrophic Lateral Sclerosis / genetics Amyotrophic Lateral Sclerosis / metabolism Animals Animals, Genetically Modified Autophagy* Carrier Proteins / genetics Carrier Proteins / metabolism* Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism* Drosophila Proteins Drosophila melanogaster / genetics Drosophila melanogaster / metabolism Gene Expression Regulation, Developmental HEK293 Cells Humans Hydrogen-Ion Concentration Lysosomes / chemistry Lysosomes / metabolism* Mutation Nervous System / growth & development Nervous System / metabolism Signal Transduction* TOR Serine-Threonine Kinases / genetics TOR Serine-Threonine Kinases / metabolism*
IF 17.728
Times Cited 22