SIRT6-dependent functional switch via K494 modifications of RE-1 silencing transcription factor.

Autor: Zaretsky A; Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel., Venzor AG; Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel., Eremenko E; Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel., Stein D; Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel., Smirnov D; Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.; Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, 121205, Russia., Rabuah Y; Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel., Dryer R; Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel., Kriukov D; Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, 121205, Russia., Kaluski-Kopatch S; Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel., Einav M; Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel., Khrameeva E; Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, 121205, Russia., Toiber D; Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel. toiber@bgu.ac.il.; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel. toiber@bgu.ac.il.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Nov 07; Vol. 15 (11), pp. 798. Date of Electronic Publication: 2024 Nov 07.
DOI: 10.1038/s41419-024-07160-0
Abstrakt: RE-1 silencing transcription factor (REST) is a key repressor of neural genes. REST is upregulated under stress signals, aging and neurodegenerative diseases, but although it is upregulated, its function is lost in Alzheimer's Disease. However, why it becomes inactive remains unclear. Here, we show that the NAD-dependent deacetylase SIRT6 regulates REST expression, location and activity. In the absence of SIRT6, REST is overexpressed but mislocalized, leading to a partial loss of its activity and causing it to become toxic. SIRT6 deficiency abrogates REST and EZH2 interaction, perturbs the location of REST to the heterochromatin Lamin B ring, and leads to REST target gene overexpression. SIRT6 reintroduction or REST methyl-mimic K494M expression rescues this phenotype, while an acetyl-mimic mutant loses its function even in WT cells. Our studies define a novel regulatory switch where, depending on SIRT6 presence, the function of REST is regulated by post-translational modifications on K494 (Ac/me), affecting neuronal gene expression. In WT cells (left), REST functions as a repressor due to its methylation, which allows proper localization and interaction with EZH2. In SIRT6 KO cells (right), REST is overexpressed, but it is mislocalized and acetylated instead of methylated, impairing its interaction with EZH2. REST localizes in the cytoplasm in autophagosomes. The overall increase in REST without SIRT6 results in non-functional and toxic REST proteins. During aging, SIRT6 declines in the brain, while REST is upregulated to protect it. In pathological aging, where SIRT6 levels are very low, the increase in REST without SIRT6 results in non-functional and toxic REST.
(© 2024. The Author(s).)
Databáze: MEDLINE
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