Journal Article

SIRT6-dependent cysteine monoubiquitination in the PRE-SET domain of Suv39h1 regulates the NF-κB pathway

Braun, Thomas, Espinosa, Lluis, Marazuela-Duque, Anna, Chen, Zhenbang, Colomer, Carlota, Vazquez, Berta N., Esteller, Manel, de la Torre, Carolina, Jenuwein, Thomas, Lu, Wenfu, Serrano, Lourdes, Martínez-Pastor, Bárbara, Barceló-Batllori, Silvia, Vaquero, Alejandro, Fuhrmann, Thomas, Bosch-Presegué, Laia, Bober, Eva, Mostoslavsky, Raúl, Santos-Barriopedro, Irene

2018

Overview

Sirtuins are NAD + -dependent deacetylases that facilitate cellular stress response. They include SirT6, which protects genome stability and regulates metabolic homeostasis through gene silencing, and whose loss induces an accelerated aging phenotype directly linked to hyperactivation of the NF-κB pathway. Here we show that SirT6 binds to the H3K9me3-specific histone methyltransferase Suv39h1 and induces monoubiquitination of conserved cysteines in the PRE-SET domain of Suv39h1. Following activation of NF-κB signaling Suv39h1 is released from the IκBα locus, subsequently repressing the NF-κB pathway. We propose that SirT6 attenuates the NF-κB pathway through IκBα upregulation via cysteine monoubiquitination and chromatin eviction of Suv39h1. We suggest a mechanism based on SirT6-mediated enhancement of a negative feedback loop that restricts the NF-κB pathway. Sirtuins are involved in the regulation of responses to diverse types of cellular stress. Here the authors describe the SirT6-dependent cysteine monoubiquitination of the histone methyltransferase Suv39h1 as part of a regulatory circuit for the NF-κB pathway.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/1 / 38/109 / 38/15 / 38/22 / 38/77 / 38/89 / 631/337/100 / 631/337/100/2285 / 631/337/176/2016 / 82/16 / 82/29 / 82/51 / 82/58 / 96/106 / 96/109 / Aging / Animals / Biology / Biomedical research / Cancer / Cell cycle / Cell Line, Tumor / Cells, Cultured / Cellular stress response / Chromatin / Chromatin - metabolism / Cromatina / Cysteine / Cysteine - genetics / Cysteine - metabolism / DNA methylation / Epigenetics / Epigenètica / Feedback loops / Gene expression / Gene silencing / Genomes / Genotype & phenotype / HCT116 Cells / HEK293 Cells / HeLa Cells / Histone methyltransferase / Histones / Homeostasis / Humanities and Social Sciences / Humans / Kinases / Laboratories / Medical research / Metabolism / Methyltransferases - genetics / Methyltransferases - metabolism / Mice / multidisciplinary / NAD / Negative feedback / NF-kappa B - metabolism / NF-KappaB Inhibitor alpha - metabolism / NF-κB protein / NIH 3T3 Cells / PR-SET Domains / Protein Binding / Proteins / Repressor Proteins - genetics / Repressor Proteins - metabolism / Research centers / Research parks / Science / Science (multidisciplinary) / Signal Transduction / Signaling / Sirtuins / Sirtuins - genetics / Sirtuins - metabolism / Ubiquitination / Up-Regulation