title: 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 coactivator-associated arginine methyltransferase 1/protein arginine methyltransferase 4 (CARM1/PRMT4) and demethylated by jumonji-domain-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.
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China; Department of Chemical and Biochemical Engineering, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361105, China;
authors.forename: Wei-wei
authors.initials: WW
authors.lastname: Gao
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China;
authors.forename: Rong-quan
authors.initials: RQ
authors.lastname: Xiao
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China;
authors.forename: Bing-ling
authors.initials: BL
authors.lastname: Peng
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China;
authors.forename: Huan-teng
authors.initials: HT
authors.lastname: Xu
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China;
authors.forename: Hai-feng
authors.initials: HF
authors.lastname: Shen
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China;
authors.forename: Ming-feng
authors.initials: MF
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China;
authors.forename: Tao-tao
authors.initials: TT
authors.lastname: Shi
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China;
authors.forename: Jia
authors.initials: J
authors.lastname: Yi
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China;
authors.forename: Wen-juan
authors.initials: WJ
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China;
authors.forename: Xiao-nan
authors.initials: XN
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China;
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Third Institute of Oceanography, State Oceanic Administration, Xiamen, Fujian 361005, China;
authors.forename: Xiang-zhi
authors.initials: XZ
authors.lastname: Lin
authors.affiliation: Department of Chemistry and Biochemistry, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Pieter C
authors.initials: PC
authors.lastname: Dorrestein
authors.affiliation: Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093 mrosenfeld@ucsd.edu w2liu@xmu.edu.cn.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China; mrosenfeld@ucsd.edu w2liu@xmu.edu.cn.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D008969:Molecular Sequence Data; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D051758:Transcription Factor TFIIH / Q000378:metabolism; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D002843:Chromatin; D018840:HSP70 Heat-Shock Proteins; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D051758:Transcription Factor TFIIH; D014212:Tretinoin; D001120:Arginine
keywords: arginine methylation; gene transcription; heat-shock proteins