Arginine methylation of HSP70 regulates retinoid acid-mediated RARβ2 gene activation

Abstract

Although "histone" methyltransferases and demethylases are well established to regulate transcriptional programs and to use nonhistone proteins as substrates, their possible roles in regulation of heat-shock proteins in the nucleus have not been investigated. Here, we report that a highly conserved arginine residue, R469, in HSP70 (heat-shock protein of 70 kDa) proteins, an evolutionarily conserved protein family of ATP-dependent molecular chaperone, was monomethylated (me1), at least partially, by coactivatorassociated arginine methyltransferase 1/protein arginine methyltransferase 4 (CARM1/PRMT4) and demethylated by jumonjidomain-containing 6 (JMJD6), both in vitro and in cultured cells. Functional studies revealed that HSP70 could directly regulate retinoid acid (RA)-induced retinoid acid receptor β2 (RARβ2) gene transcription through its binding to chromatin, with R469me1 being essential in this process. HSP70's function in gene transcriptional regulation appears to be distinct from its protein chaperon activity. R469me1 was shown to mediate the interaction between HSP70 and TFIIH, which involves in RNA polymerase II phosphorylation and thus transcriptional initiation. Our findings expand the repertoire of nonhistone substrates targeted by PRMT4 and JMJD6, and reveal a new function of HSP70 proteins in gene transcription at the chromatin level aside from its classic role in protein folding and quality control.heat-shock proteins | arginine methylation | gene transcription

JMJD6 Licenses ERα-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/MED12 Co-activator Complex

“…5G). The activities of all PRMTs have been described in our previous report (Gao et al, 2015). Next, we attempted to identify the arginine methylation sites at C-terminus of MED12, which are presumably catalyzed by CARM1, and examine the change of such methylation in response to JMJD6 depletion using the MS data collected above in both wild type and JMJD6 knockout cells.…”

“…Subsequent studies demonstrated that it was localized in the nucleus of a cell, suggesting it might possess novel nuclear functions (Hahn et al, Cikala et al, 2004, Hahn et al, 2010, Cui et al, 2004, Tibrewal et al, 2007). JMJD6 was found to function as an iron (Fe 2+ )- and 2-oxoglutarate (2-OG)-dependent dioxygenase that demethylates methylated arginines as well as hydroxylates lysines on both histone and non-histone proteins (Chang et al, 2007, Liu et al, 2013, Poulard et al, 2014, Lawrence et al, 2014, Gao et al, 2015, Wu et al, 2015, Tikhanovich et al, 2015, Mantri et al, 2011, Unoki et al, 2013, Webby et al, 2009, Wang et al, 2014a). We recently reported a transcriptional paradigm in which JMJD6 regulates promoter-proximal Pol II pausing release in a distal manner (Liu et al, 2013).…”

Jumonji domain‐containing protein 6 protein and its role in cancer

“…Notably, JMJD6 demethylates monomethylarginine and symmetric and asymmetric dimethylarginine residues (Figure A). Recent studies found that JMJD6 also targets arginine residues of non‐histone proteins for demethylation, including RNA helicase A, oestrogen receptor α (ERα), tumour necrosis factor receptor‐associated factor 6 (TRAF6), the transcription factor PAX3 and heat‐shock protein 70 (HSP70) …”

An asymmetrically dimethylarginated nuclear 90 kDa protein (p90aDMA) induced by interleukin (IL)-2, IL-4 or IL-6 in the tumor microenvironment is selectively degraded by autophagy

“…PRMT1 and PRMT5 are the major asymmetric and symmetric arginine methyltransferases, respectively (25). Arginine methylation has received increasing attention over the last years as several recent reports have illustrated a novel role for this posttranslational modification in regulating proteinprotein interaction and transcriptional induction (26,27), and is often deregulated in cancer (25). However, how arginine methylation could be regulated by interleukins or autophagy in the context of the tumor microenvironment has not yet been investigated.…”