UCL Institute of Ophthalmology, London, United Kingdom.
PLoS One. 2012;7(2):e30866. doi: 10.1371/journal.pone.0030866. Epub 2012 Feb 7.
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.
AIPL1 中的突变会导致遗传性失明莱伯先天性黑蒙症（LCA）。此前已经表明，AIPL1 与 NUB1 相互作用，促进了被泛素样蛋白 FAT10 修饰的蛋白质的蛋白酶体降解。在这里，我们报告 AIPL1 与游离的 FAT10 和 FAT10 化蛋白非共价结合，并能与 FAT10 和 NUB1 形成三元复合物。此外，AIPL1 拮抗了 NUB1 介导的 FAT10 模型缀合物 FAT10-DHFR 的降解，并且 AIPL1 的致病性突变在抑制这种降解方面存在缺陷。虽然所有测试的 AIPL1 突变体仍与 FAT10-DHFR 结合，但突变体与 NUB1 相互作用的能力与其阻止 NUB1 介导的降解的能力之间存在密切的相关性。有趣的是，AIPL1 还与 FAT10 的 E1 激活酶 UBA6 共免疫沉淀，这表明 AIPL1 可能在直接调节 FAT10 缀合机制中发挥作用。这些研究首次将 FAT10 与视网膜细胞生物学和 LCA 发病机制联系起来，并揭示了 AIPL1 在调节 FAT10 途径中的新作用。
