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

Abstract

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.

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HDAC8 affects MGMT levels in glioblastoma cell lines via interaction with the proteasome receptor ADRM1

“…Protein extraction was performed using a modified Dignam method, as described previously [44, 45]. Briefly, a cytoplasmic extraction was made with buffer A (10 mM Tris pH 7.8; 10 mM KCl; 1.5 mM MgCl 2 ) and a nucleoplasmic extraction was made with buffer C (10 mM Tris pH 7.8; 0.42 M NaCl; 1.5 mM MgCl 2 ; 0.2 mM EDTA; 25% glycerol).…”

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“…SIRT1 regulates H3K9 methylation by deacetylating K266 in the Su(var)3-9, enhancer-of-zeste and trithorax (SET) domain of SUV39H1, thus increasing its activity during heterochromatin formation (Shankaranarayana et al, 2003;Vaquero et al, 2007). While SIRT6 induces the monoubiquitination of cysteines (Cys) in the pre-SET domain of SUV39H1, removing SUV39H1 from IκBα negatively regulates the nuclear factor-kappaB (NF-κB) pathway (Santos-Barriopedro et al, 2018). Depsipeptide decreases H3K9me2/3 expression by reducing the expression of SUV39H1 and G9A (also called KMT1C) (Wu et al, 2008).…”