title: The inherited blindness protein AIPL1 regulates the ubiquitin-like FAT10 pathway.
abstract: 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.
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: John S
authors.initials: JS
authors.lastname: Bett
authors.forename: Naheed
authors.initials: N
authors.lastname: Kanuga
authors.forename: Emma
authors.initials: E
authors.lastname: Richet
authors.forename: Gunter
authors.initials: G
authors.lastname: Schmidtke
authors.forename: Marcus
authors.initials: M
authors.lastname: Groettrup
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.forename: Jacqueline
authors.initials: J
authors.lastname: van der Spuy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D005136:Eye Proteins / Q000502:physiology*; D006801:Humans; D057130:Leber Congenital Amaurosis; D009154:Mutation; D012160:Retina / Q000473:pathology; D014157:Transcription Factors; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: C403625:AIPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D005136:Eye Proteins; C430242:NUB1 protein, human; D014157:Transcription Factors; C109184:UBD protein, human; D014452:Ubiquitins