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

Irene Santos-Barriopedro, Laia Bosch-Presegué, Anna Marazuela-Duque, Carolina de la Torre, Carlota Colomer, Berta N. Vazquez, Thomas Fuhrmann, Bárbara Martínez-Pastor, Wenfu Lu, Thomas Braun, Eva Bober, Thomas Jenuwein, Lourdes Serrano, Manel Esteller, Zhenbang Chen, Silvia Barceló-Batllori, Raúl Mostoslavsky, Lluis Espinosa and Alejandro Vaquero ()
Additional contact information
Irene Santos-Barriopedro: Bellvitge Biomedical Research Institute (IDIBELL)
Laia Bosch-Presegué: Bellvitge Biomedical Research Institute (IDIBELL)
Anna Marazuela-Duque: Bellvitge Biomedical Research Institute (IDIBELL)
Carolina de la Torre: Bellvitge Biomedical Research Institute (IDIBELL)
Carlota Colomer: IMIM-Hospital del Mar, Barcelona Biomedical Research Park (PRBB)
Berta N. Vazquez: The State University of New Jersey
Thomas Fuhrmann: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51
Bárbara Martínez-Pastor: Harvard Medical School
Wenfu Lu: Meharry Medical College
Thomas Braun: Max-Planck-Institute for Heart and Lung Research
Eva Bober: Max-Planck-Institute for Heart and Lung Research
Thomas Jenuwein: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51
Lourdes Serrano: The State University of New Jersey
Manel Esteller: Bellvitge Biomedical Research Institute (IDIBELL)
Zhenbang Chen: Meharry Medical College
Silvia Barceló-Batllori: Bellvitge Biomedical Research Institute (IDIBELL)
Raúl Mostoslavsky: Harvard Medical School
Lluis Espinosa: IMIM-Hospital del Mar, Barcelona Biomedical Research Park (PRBB)
Alejandro Vaquero: Bellvitge Biomedical Research Institute (IDIBELL)

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02586-x

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