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CLN3 regulates endosomal function by modulating Rab7A effector interactions


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Yasa, Seda; Modica, Graziana; Sauvageau, Etienne; Kaleem, Abuzar; Hermey, Guido et Lefrancois, Stephane ORCID logoORCID: https://orcid.org/0000-0002-3312-9594 (2020). CLN3 regulates endosomal function by modulating Rab7A effector interactions Journal of Cell Science , vol. 133 , nº 6. pp. 1-14. DOI: 10.1242/jcs.23404.

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Mutations in CLN3 are a cause of juvenile neuronal ceroid lipofuscinosis (JNCL), also known as Batten Disease. Clinical manifestations includes cognitive regression, progressive loss of vision and motor function, epileptic seizures, and a significantly reduced lifespan. CLN3 localizes to endosomes and lysosomes, and has been implicated in intracellular trafficking and autophagy. However, the precise molecular function of CLN3 remains to be elucidated. Previous studies showed an interaction between CLN3 and Rab7A, a small GTPase that regulates several functions at late endosomes. We confirmed this interaction in live cells and found that CLN3 is required for the efficient endosome-to-TGN trafficking of the lysosomal sorting receptors by regulating the Rab7A/retromer interaction. In cells lacking CLN3 or expressing CLN3 harbouring a disease-causing mutation, the lysosomal sorting receptors were degraded. We also demonstrated that CLN3 is required for the Rab7A/PLEKHM1 interaction, which is required for autophagosome/lysosome fusion. Overall, our data provide a molecular explanation behind phenotypes observed in JNCL and give an indication to the pathogenic mechanism behind Batten disease.

Type de document: Article
Mots-clés libres: CLN3; Endosomes; Juvenile neuronal ceroid lipofuscinosis; Rab7A; Retromer; Sortilin
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 20 juill. 2021 21:43
Dernière modification: 15 févr. 2022 19:19
URI: https://espace.inrs.ca/id/eprint/11714

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