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The ubiquitin-like modifier FAT10 inhibits retinal PDE6 activity and mediates its proteasomal degradation

Boehm, AN; Bialas, J; Catone, N; Sacristan-Reviriego, A; Van der Spuy, J; Groettrup, M; Aichem, A; (2020) The ubiquitin-like modifier FAT10 inhibits retinal PDE6 activity and mediates its proteasomal degradation. Journal of Biological Chemistry , 295 (42) pp. 14402-14418. 10.1074/jbc.RA120.013873. Green open access

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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.

Type: Article
Title: The ubiquitin-like modifier FAT10 inhibits retinal PDE6 activity and mediates its proteasomal degradation
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1074/jbc.RA120.013873
Publisher version: https://doi.org/10.1074/jbc.RA120.013873
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: AIPL1, FAT10, PDE6, cell culture, chaperone, cyclic GMP (cGMP), phosphodiesterases, photoreceptor, proteasome, protein processing, protein stability, protein turnover, retina, retinal degeneration, ubiquitin-like protein, ubiquitylation (ubiquitination)
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
URI: https://discovery.ucl.ac.uk/id/eprint/10112976
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