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Abstract：
The retina-specific chaperone aryl hydrocarbon interacting protein-like 1 (AIPL1) is essential for the correct assembly of phosphodiesterase 6 (PDE6), which is a pivotal effector enzyme for phototransduction and vision because it hydrolyzes cGMP. AIPL1 interacts with the cytokine-inducible ubiquitin-like modifier FAT10, which gets covalently conjugated to hundreds of proteins and targets its conjugation substrates for proteasomal degradation, but whether FAT10 affects PDE6 function or turnover is unknown. Here, we show that FAT10 mRNA is expressed in human retina and identify rod PDE6 as a retina-specific substrate of FAT10 conjugation. We found that AIPL1 stabilizes the FAT10 monomer and the PDE6-FAT10 conjugate. Additionally, we elucidated the functional consequences of PDE6 FAT10ylation. On the one hand, we demonstrate that FAT10 targets PDE6 for proteasomal degradation by formation of a covalent isopeptide linkage. On the other hand, FAT10 inhibits PDE6 cGMP hydrolyzing activity by noncovalently interacting with the PDE6 GAFa and catalytic domains. Therefore, FAT10 may contribute to loss of PDE6 and, as a consequence, degeneration of retinal cells in eye diseases linked to inflammation and inherited blindness-causing mutations in AIPL1.
摘要：
视网膜特异性伴侣芳基烃相互作用蛋白样1（AIPL1）对于正确组装磷酸二酯酶6（PDE6）至关重要，它是光转导和视觉的关键效应酶，因为它水解cGMP。AIPL1与细胞因子诱导的泛素样修饰剂FAT10相互作用，该修饰剂与数百种蛋白质共价缀合，并靶向其缀合底物进行蛋白酶体降解，但FAT10是否影响PDE6的功能或周转是未知的。这里,我们显示FAT10mRNA在人视网膜中表达，并将杆PDE6鉴定为FAT10缀合的视网膜特异性底物。我们发现AIPL1稳定FAT10单体和PDE6-FAT10缀合物。此外,我们阐明了PDE6FAT10酰化的功能后果。一方面,我们证明FAT10通过形成共价异肽键而靶向PDE6进行蛋白酶体降解。另一方面,FAT10通过与PDE6GAFA和催化结构域非共价相互作用抑制PDE6cGMP水解活性。因此,FAT10可能导致PDE6的损失，因此，眼病中视网膜细胞的变性与AIPL1的炎症和遗传性致盲突变有关。
