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Nat Cell Biol. 2019 Mar;21(3):384-396. doi: 10.1038/s41556-019-0281-x. Epub 2019 Feb 25.

Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification.

Author information

1
Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX, USA.
2
Department of Molecular and Human Genetics, BCM, Houston, TX, USA.
3
Department of Bioengineering, Rice University, Houston, TX, USA.
4
Medical Scientist Training Program, BCM, Houston, TX, USA.
5
Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.
6
Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX, USA. hbellen@bcm.edu.
7
Department of Molecular and Human Genetics, BCM, Houston, TX, USA. hbellen@bcm.edu.
8
Department of Neuroscience, BCM, Houston, TX, USA. hbellen@bcm.edu.
9
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA. hbellen@bcm.edu.
10
Howard Hughes Medical Institute, BCM, Houston, TX, USA. hbellen@bcm.edu.

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.

PMID:
30804504
PMCID:
PMC6534127
DOI:
10.1038/s41556-019-0281-x
[Indexed for MEDLINE]

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