The Batten disease protein CLN3 is important for stress granules dynamics and translational activity
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The Batten disease protein CLN3 is important for stress granules dynamics and translational activity. / Relton, Emily L; Roth, Nicolas J; Yasa, Seda; Kaleem, Abuzar; Hermey, Guido; Minnis, Christopher J; Mole, Sara E; Shelkovnikova, Tatyana; Lefrancois, Stephane; McCormick, Peter J; Locker, Nicolas.
in: J BIOL CHEM, Jahrgang 299, Nr. 5, 05.2023, S. 104649.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - The Batten disease protein CLN3 is important for stress granules dynamics and translational activity
AU - Relton, Emily L
AU - Roth, Nicolas J
AU - Yasa, Seda
AU - Kaleem, Abuzar
AU - Hermey, Guido
AU - Minnis, Christopher J
AU - Mole, Sara E
AU - Shelkovnikova, Tatyana
AU - Lefrancois, Stephane
AU - McCormick, Peter J
AU - Locker, Nicolas
N1 - Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2023/5
Y1 - 2023/5
N2 - The assembly of membrane-less organelles such as stress granules (SGs) is emerging as central in helping cells rapidly respond and adapt to stress. Following stress sensing, the resulting global translational shutoff leads to the condensation of stalled mRNAs and proteins into SGs. By reorganizing cytoplasmic contents, SGs can modulate RNA translation, biochemical reactions, and signaling cascades to promote survival until the stress is resolved. While mechanisms for SG disassembly are not widely understood, the resolution of SGs is important for maintaining cell viability and protein homeostasis. Mutations that lead to persistent or aberrant SGs are increasingly associated with neuropathology and a hallmark of several neurodegenerative diseases. Mutations in CLN3 are causative of juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease affecting children also known as Batten disease. CLN3 encodes a transmembrane lysosomal protein implicated in autophagy, endosomal trafficking, metabolism, and response to oxidative stress. Using a HeLa cell model lacking CLN3, we now show that CLN3KO is associated with an altered metabolic profile, reduced global translation, and altered stress signaling. Furthermore, loss of CLN3 function results in perturbations in SG dynamics, resulting in assembly and disassembly defects, and altered expression of the key SG nucleating factor G3BP1. With a growing interest in SG-modulating drugs for the treatment of neurodegenerative diseases, novel insights into the molecular basis of CLN3 Batten disease may reveal avenues for disease-modifying treatments for this debilitating childhood disease.
AB - The assembly of membrane-less organelles such as stress granules (SGs) is emerging as central in helping cells rapidly respond and adapt to stress. Following stress sensing, the resulting global translational shutoff leads to the condensation of stalled mRNAs and proteins into SGs. By reorganizing cytoplasmic contents, SGs can modulate RNA translation, biochemical reactions, and signaling cascades to promote survival until the stress is resolved. While mechanisms for SG disassembly are not widely understood, the resolution of SGs is important for maintaining cell viability and protein homeostasis. Mutations that lead to persistent or aberrant SGs are increasingly associated with neuropathology and a hallmark of several neurodegenerative diseases. Mutations in CLN3 are causative of juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease affecting children also known as Batten disease. CLN3 encodes a transmembrane lysosomal protein implicated in autophagy, endosomal trafficking, metabolism, and response to oxidative stress. Using a HeLa cell model lacking CLN3, we now show that CLN3KO is associated with an altered metabolic profile, reduced global translation, and altered stress signaling. Furthermore, loss of CLN3 function results in perturbations in SG dynamics, resulting in assembly and disassembly defects, and altered expression of the key SG nucleating factor G3BP1. With a growing interest in SG-modulating drugs for the treatment of neurodegenerative diseases, novel insights into the molecular basis of CLN3 Batten disease may reveal avenues for disease-modifying treatments for this debilitating childhood disease.
U2 - 10.1016/j.jbc.2023.104649
DO - 10.1016/j.jbc.2023.104649
M3 - SCORING: Journal article
C2 - 36965618
VL - 299
SP - 104649
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 5
ER -