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

2018; Nature Portfolio; Volume: 9; Issue: 1 Linguagem: Inglês

10.1038/s41467-017-02586-x

2041-1723

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

Calcium signaling and nucleotide metabolism

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.