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Şentürk, M., Lin, G., Zuo, Z., Mao, D., Watson, E., Mikos, A.G., Bellen, H.J. (2019). Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification.  Nat. Cell Biol. 21(3): 384--396.
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Research paper

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.

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PubMed Central ID
PMC6534127 (PMC) (EuropePMC)
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    Publication Type
    Nat. Cell Biol.
    Nature Cell Biology
    Publication Year
    1465-7392 1476-4679
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    Aberrations (1)
    Alleles (22)
    Genes (34)
    Human Disease Models (2)
    Polypeptides (1)
    Natural transposons (1)
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