Santos-Barriopedro Irene, Bosch-Presegué Laia, Marazuela-Duque Anna, de la Torre Carolina, Colomer Carlota, Vazquez Berta N, Fuhrmann Thomas, Martínez-Pastor Bárbara, Lu Wenfu, Braun Thomas, Bober Eva, Jenuwein Thomas, Serrano Lourdes, Esteller Manel, Chen Zhenbang, Barceló-Batllori Silvia, Mostoslavsky Raúl, Espinosa Lluis, Vaquero Alejandro
Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Via de l'Hospitalet 199-203, 08908, L'Hospitalet de Llobregat (Barcelona), Spain.
Tissue Repair and Regeneration Group, Department of Biosciences, Universitat de Vic, Universitat Central de Catalunya, Barcelona, 08500, Vic, Spain.
Nat Commun. 2018 Jan 9;9(1):101. doi: 10.1038/s41467-017-02586-x.
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.
沉默调节蛋白是依赖烟酰胺腺嘌呤二核苷酸（NAD）的去乙酰化酶，可促进细胞应激反应。它们包括SirT6，其通过基因沉默保护基因组稳定性并调节代谢稳态，其缺失会诱导与NF-κB通路过度激活直接相关的加速衰老表型。在此，我们表明SirT6与H3K9me3特异性组蛋白甲基转移酶Suv39h1结合，并诱导Suv39h1的PRE-SET结构域中保守半胱氨酸的单泛素化。在NF-κB信号激活后，Suv39h1从IκBα基因座释放，随后抑制NF-κB通路。我们提出，SirT6通过半胱氨酸单泛素化和Suv39h1的染色质驱逐上调IκBα来减弱NF-κB通路。我们提出了一种基于SirT6介导的增强负反馈回路的机制，该回路限制了NF-κB通路。
