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CLN5 and CLN3 func3on as a complex to regulate endosome-to-TGN trafficking

Yasa, Seda; Sauvageau, Etienne; Modica, Graziana et Lefrancois, Stephane . CLN5 and CLN3 func3on as a complex to regulate endosome-to-TGN trafficking In: Sanford CoRDS Great Plains Rare Disease Day Summit, 16 october 2020, Sioux Falls, SD.

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Abstract: Mutations in the CLN5 and CLN3 genes are the cause of a rare neurodegenerative disorder called neuronal ceroid lipofuscinosis, more commonly referred to as Batten disease. CLN5 is a soluble endolysosomal protein, while CLN3 is an integral membrane protein localized to the same compartment. Previously we have shown that both CLN5 and CLN3 are required for the recruitment of retromer to endosomal membranes. However, how a soluble lysosomal protein (CLN5) can modulate recruitment of a protein in the cytosol is not known. Furthermore, the impact of disease-causing mutations in CLN5 on this process have not been studied. Retromer is a protein complex that mediates the endosome-to-trans Golgi Network (TGN) trafficking of the lysosomal sorting receptor sortilin, under the regulation of the small GTPase Rab7A. GTP bound Rab7 is localized to late endosomes and regulates the spatiotemporal recruitment of retromer, the degradation of integral membrane proteins such as epidermal growth factor (EGF) receptor (EGFR), lysosomal positioning, and also participates in autophagosome-lysosome fusion through HOPS complex, thereby regulating autophagy. Our previous work demonstrated that silencing of CLN5 using siRNA resulted in the degradation of sortilin as a result of inefficient retromer membrane recruitment. Recently, we have shown that CLN3 is also required in the endosome-to-TGN trafficking of the lysosomal sorting receptors. Studies have shown that CLN3 can interact with other CLN proteins including CLN5, however the molecular function of this interaction is not known. In this work, we engineered a CLN5 knockout HeLa cell line using CRIPSR/Cas9. We showed that CLN5 is required for the palmitoylation of Rab7A, which is required for the efficient recruitment and function of retromer. We found that sortilin is degraded in CLN5 knockout HeLa cells. CLN3 is also required for the endosome-to-TGN sorting of sortilin by interacting with sortilin, a step required for the sortilin/retromer interaction. The CLN3/sortilin interaction was disrupted in CLN5 knockout HeLa cells. This suggests that CLN5 and CLN3 function as a complex at endosomes to coordinate the sorting of sortilin. In summary, we demonstrate a role for CLN5/CLN3 as a complex on the sorting of sortilin and the effects of CLN5 disease-causing mutations on this function

Type de document: Document issu d'une conférence ou d'un atelier
Informations complémentaires: Affiche électronique avec présentation https://vimeo.com/465939742
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 14 juill. 2021 15:49
Dernière modification: 14 juill. 2021 15:49
URI: https://espace.inrs.ca/id/eprint/11840

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