ArticleHuman molecular genetics2016
FIG4 regulates lysosome membrane homeostasis independent of phosphatase function.
Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 52 citations in OpenAlex.
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- Non-cell autonomous autophagy in amyotrophic lateral sclerosis: A new promising target?Neurobiology of disease · 2026Review
- Homeostatic Influence of Fig4 Outside of the Fab1-Vac14-Fig4 Complex in Saccharomyces cerevisiae.Molecular microbiology · 2025Article
- Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis.Molecular neurobiology · 2025Review
- The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Autophagy reports · 2025Review
- The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association · 2024Review
- The endolysosomal pathway and ALS/FTD.Trends in neurosciences · 2023Review
- Autophagic lysosome reformation in health and disease.Autophagy · 2023Review
- Activation of eIF4E-binding-protein-1 rescues mTORC1-induced sarcopenia by expanding lysosomal degradation capacity.Journal of cachexia, sarcopenia and muscle · 2023Article
- A nerve-wracking buzz: lessons fromFrontiers in aging neuroscience · 2023Review
- Bioactive Components and Health Potential of Endophytic Micro-Fungal Diversity in Medicinal Plants.Antibiotics (Basel, Switzerland) · 2022Article
- Autophagy Dysfunction in ALS: from Transport to Protein Degradation.Journal of molecular neuroscience : MN · 2022Review
- The Interplay Between Autophagy and RNA Homeostasis: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.Frontiers in cell and developmental biology · 2022Review
- A novel phosphoinositide kinase Fab1 regulates biosynthesis of pathogenic aflatoxin inVirulence · 2021Article
- Held Up in Traffic-Defects in the Trafficking Machinery in Charcot-Marie-Tooth Disease.Frontiers in molecular neuroscience · 2021Review
- Article
- A dysfunctional endolysosomal pathway common to two sub-types of demyelinating Charcot-Marie-Tooth disease.Acta neuropathologica communications · 2020Article
- Recent Advances inInternational journal of molecular sciences · 2020Review
- Roles for a lipid phosphatase in the activation of its opposing lipid kinase.Molecular biology of the cell · 2020Article
- Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
FIG4 is a phosphoinositide phosphatase that is mutated in several diseases including Charcot-Marie-Tooth Disease 4J (CMT4J) and Yunis-Varon syndrome (YVS). To investigate the mechanism of disease pathogenesis, we generated Drosophila models of FIG4-related diseases. Fig4 null mutant animals are viable but exhibit marked enlargement of the lysosomal compartment in muscle cells and neurons, accompanied by an age-related decline in flight ability. Transgenic animals expressing Drosophila Fig4 missense mutations corresponding to human pathogenic mutations can partially rescue lysosomal expansion phenotypes, consistent with these mutations causing decreased FIG4 function. Interestingly, Fig4 mutations predicted to inactivate FIG4 phosphatase activity rescue lysosome expansion phenotypes, and mutations in the phosphoinositide (3) phosphate kinase Fab1 that performs the reverse enzymatic reaction also causes a lysosome expansion phenotype. Since FIG4 and FAB1 are present together in the same biochemical complex, these data are consistent with a model in which FIG4 serves a phosphatase-independent biosynthetic function that is essential for lysosomal membrane homeostasis. Lysosomal phenotypes are suppressed by genetic inhibition of Rab7 or the HOPS complex, demonstrating that FIG4 functions after endosome-to-lysosome fusion. Furthermore, disruption of the retromer complex, implicated in recycling from the lysosome to Golgi, does not lead to similar phenotypes as Fig4, suggesting that the lysosomal defects are not due to compromised retromer-mediated recycling of endolysosomal membranes. These data show that FIG4 plays a critical noncatalytic function in maintaining lysosomal membrane homeostasis, and that this function is disrupted by mutations that cause CMT4J and YVS.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.