X.-D. Yang, E. Tajkhorshid, and L.-F. Chen.
Functional interplay between acetylation and methylation of the
RelA subunit of NF-κB.
Molecular and Cellular Biology, 30:2170-2180, 2010.
YANG2010-ET
Posttranslational modifications of the RelA subunit of NF-B, including acetylation and
methylation, play a key role in controlling the strength and duration of its nuclear activity.
Whether these modifications are functionally linked is largely unknown. Here, we show that
the acetylation of lysine 310 of RelA impairs the Set9-mediated methylation of lysines 314
and 315, which is important for the ubiquitination and degradation of chromatin-
associated RelA. Abolishing the acetylation of lysine 310 either by the deacetylase SIRT1 or
by mutating lysine 310 to arginine enhances methylation. Conversely, enhancing the
acetylation of lysine 310 by depleting SIRT1 or by replacing lysine 310 with acetyl-mimetic
glutamine inhibits methylation, thereby decreasing ubiquitination, prolonging the stability
of chromatin-associated RelA, and enhancing the transcriptional activity of NF-B. The
acetylation of lysine 310 of RelA interferes with its interaction with Set9. Based on
structural modeling of the SET domain of Set9 with RelA, we propose that the positive
charge of lysine 310 is critical for the binding of RelA to a negatively charged “exosite”
within the SET domain of Set9. Together, these findings demonstrate for the first time an
interplay between RelA acetylation and methylation and also provide a novel mechanism
for the regulation of lysine methylation by acetylation.
