The inherited blindness protein AIPL1 regulates the ubiquitin-like FAT10 pathway

Mutations in AIPL1 cause the inherited blindness Leber congenital amaurosis (LCA). AIPL1 has previously been shown to interact with NUB1, which facilitates the proteasomal degradation of proteins modified with the ubiquitin-like protein FAT10. Here we report that AIPL1 binds non-covalently to free F...

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Bibliographic Details
Published in:PloS one 2012-02, Vol.7 (2), p.e30866-e30866
Main Authors: Bett, John S, Kanuga, Naheed, Richet, Emma, Schmidtke, Gunter, Groettrup, Marcus, Cheetham, Michael E, van der Spuy, Jacqueline
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Analysis
Biodegradation
Biology
Blindness
Carrier Proteins - physiology
Cell Line, Tumor
Cells (Biology)
Conjugation
Cytokines
Degradation
Dihydrofolate reductase
Enzymes
Eye Proteins - physiology
Gynecology
Humans
Immunoglobulins
Immunology
Leber Congenital Amaurosis
Liver cancer
Machinery and equipment
Medicine
Mutants
Mutation
Pathogenesis
Photoreceptors
Physiology
Plasmids
Proteasomes
Proteins
Proteolysis
Retina
Retina - pathology
Tetrahydrofolate dehydrogenase
Transcription Factors
Ubiquitin
Ubiquitins - metabolism
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Summary:Mutations in AIPL1 cause the inherited blindness Leber congenital amaurosis (LCA). AIPL1 has previously been shown to interact with NUB1, which facilitates the proteasomal degradation of proteins modified with the ubiquitin-like protein FAT10. Here we report that AIPL1 binds non-covalently to free FAT10 and FAT10ylated proteins and can form a ternary complex with FAT10 and NUB1. In addition, AIPL1 antagonised the NUB1-mediated degradation of the model FAT10 conjugate, FAT10-DHFR, and pathogenic mutations of AIPL1 were defective in inhibiting this degradation. While all AIPL1 mutants tested still bound FAT10-DHFR, there was a close correlation between the ability of the mutants to interact with NUB1 and their ability to prevent NUB1-mediated degradation. Interestingly, AIPL1 also co-immunoprecipitated the E1 activating enzyme for FAT10, UBA6, suggesting AIPL1 may have a role in directly regulating the FAT10 conjugation machinery. These studies are the first to implicate FAT10 in retinal cell biology and LCA pathogenesis, and reveal a new role of AIPL1 in regulating the FAT10 pathway.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0030866