Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification
Open accessAbstract
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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UBQLN2 modulates MTORC1 activity, lysosomal acidification, and autophagosome maturation.
“UBQLN2 modulates MTORC1 activity, lysosomal acidification, and, in turn, autophagosome maturation [229–231].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [229]
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- Authors
- Şentürk, M., Lin, G., Zuo, Z., Mao, D., Watson, E., Mikos, A. G., & Bellen, H. J.
- Affiliations
- Baylor College of Medicine (US)
- Rice University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Bellen, Hugo J.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2019-02-25
- Volume
- 21
- Issue
- 3
- Pages
- 384-396
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC6534127
- OpenAlex
- W2916733639
- Cited by
- 124
- References
- 63
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 10 · 2023: 10 · 2022: 16 · 2021: 28 · 2020: 31 · 2019: 9
- FWCI
- 15.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P40OD018537, R24OD022005)
- National Cancer Institute (P30CA125123)
- National Institute of General Medical Sciences (R01GM067858)
- National Institute of Dental and Craniofacial Research (F31DE027586)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083092)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- ubiquilin, UBQLN2, amyotrophic lateral sclerosis, autophagic flux, mTOR signaling, mTORC1, lysosomal acidification, vacuolar H+-ATPase, endoplasmic reticulum stress, proteostasis, neuronal cell death, Drosophila
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, Autophagy, Carrier Proteins, Drosophila melanogaster, Humans, Hydrogen-Ion Concentration, Lysosomes, Mutation, Nervous System, Signal Transduction, Gene Expression Regulation, Developmental, Cell Cycle Proteins, Drosophila Proteins, Animals, Genetically Modified, HEK293 Cells, TOR Serine-Threonine Kinases
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