CLN3 regulates endosomal function by modulating Rab7A effector interactions
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CLN3 regulates endosomal function by modulating Rab7A effector interactions. / Yasa, Seda; Modica, Graziana; Sauvageau, Etienne; Kaleem, Abuzar; Hermey, Guido; Lefrancois, Stephane.
In: J CELL SCI, Vol. 133, No. 6, 16.03.2020.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - CLN3 regulates endosomal function by modulating Rab7A effector interactions
AU - Yasa, Seda
AU - Modica, Graziana
AU - Sauvageau, Etienne
AU - Kaleem, Abuzar
AU - Hermey, Guido
AU - Lefrancois, Stephane
N1 - © 2020. Published by The Company of Biologists Ltd.
PY - 2020/3/16
Y1 - 2020/3/16
N2 - Mutations in CLN3 are a cause of juvenile neuronal ceroid lipofuscinosis (JNCL), also known as Batten disease. Clinical manifestations include 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 because it regulates the Rab7A interaction with retromer. 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 fusion of autophagosomes to lysosomes. Overall, our data provide a molecular explanation behind phenotypes observed in JNCL and give an indication of the pathogenic mechanism behind Batten disease.This article has an associated First Person interview with the first author of the paper.
AB - Mutations in CLN3 are a cause of juvenile neuronal ceroid lipofuscinosis (JNCL), also known as Batten disease. Clinical manifestations include 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 because it regulates the Rab7A interaction with retromer. 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 fusion of autophagosomes to lysosomes. Overall, our data provide a molecular explanation behind phenotypes observed in JNCL and give an indication of the pathogenic mechanism behind Batten disease.This article has an associated First Person interview with the first author of the paper.
U2 - 10.1242/jcs.234047
DO - 10.1242/jcs.234047
M3 - SCORING: Journal article
C2 - 32034082
VL - 133
JO - J CELL SCI
JF - J CELL SCI
SN - 0021-9533
IS - 6
ER -