Histone malonylation is regulated by SIRT5 and KAT2A
Ran Zhang,
Joanna Bons,
Grace Scheidemantle,
Xiaojing Liu,
Olga Bielska,
Chris Carrico,
Jacob Rose,
Indra Heckenbach,
Morten Scheibye-Knudsen,
Birgit Schilling,
Eric Verdin
Affiliations
Ran Zhang
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
Joanna Bons
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
Grace Scheidemantle
Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA
Xiaojing Liu
Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA
Olga Bielska
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
Chris Carrico
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
Jacob Rose
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
Indra Heckenbach
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA; Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Nørregade 10, Copenhagen, Denmark
Morten Scheibye-Knudsen
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Nørregade 10, Copenhagen, Denmark
Birgit Schilling
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
Eric Verdin
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA; Corresponding author
Summary: The posttranslational modification lysine malonylation is found in many proteins, including histones. However, it remains unclear whether histone malonylation is regulated or functionally relevant. Here, we report that availability of malonyl-co-enzyme A (malonyl-CoA), an endogenous malonyl donor, affects lysine malonylation, and that the deacylase SIRT5 selectively reduces malonylation of histones. To determine if histone malonylation is enzymatically catalyzed, we knocked down each of the 22 lysine acetyltransferases (KATs) to test their malonyltransferase potential. KAT2A knockdown in particular reduced histone malonylation levels. By mass spectrometry, H2B_K5 was highly malonylated and regulated by SIRT5 in mouse brain and liver. Acetyl-CoA carboxylase (ACC), the malonyl-CoA producing enzyme, was partly localized in the nucleolus, and histone malonylation increased nucleolar area and ribosomal RNA expression. Levels of global lysine malonylation and ACC expression were higher in older mouse brains than younger mice. These experiments highlight the role of histone malonylation in ribosomal gene expression.
