PNAS：厦门大学表观遗传学新文章

热休克蛋白(HSPs)又称应激蛋白(SP)，是机体细胞在一些应激原如环境高温、缺氧、重金属中毒、氧化应激、感染、饥饿、创伤、代谢毒物等条件诱导下，激活HSP基因，高效表达的一组进化上高度保守的蛋白质，对机体免受应激因素的损害具有重要作用。近来的研究确立了一些“组蛋白”甲基转移酶和去甲基化酶调控了转录程序，并利用了非组蛋白来作为底物，但尚未深入调查它们对细胞核中HSPs的调控作用。

根据分子量的大小HSPs可分为以下几个家族，即HSP100、HSP90、HSP70、HSP60以及小HSP。HSP70是热休克蛋白家族中最为重要的一族，有20余个成员，进化上高度保守。HSP70作为一种非特异性的细胞保护蛋白，是目前发现的主要分子伴侣蛋白之一，可维持细胞蛋白自稳，提高细胞对应激原的耐受性，使细胞维持正常的生理功能。HSP70分布广泛，参与许多细胞的正常生理过程，直接参与了蛋白质从初生链合成到多亚基复合体折叠、装配的整个生物合成，并参与了蛋白质向内质网的易位、参与了分解错装的蛋白质等，并与新生肽和多肽链中错配的部分结合，对调节蛋白质内环境的稳定具有重要作用。

在这篇文章中研究人员报告称发现，在体外和培养细胞中CARM1/PRMT4和JMJD6可分别使得HSP70的高度保守精氨酸残基R469单甲基化和脱甲基化。功能研究揭示HSP70可通过结合染色质直接调控维甲酸(RA)诱导的RARβ2基因转录，R469甲基化是这一过程的必要条件。HSP70在基因转录调控中所起的作用似乎不同于它的分子伴侣蛋白活性。研究人员证实R469甲基化介导了HSP70与TFIIH直接的互作，后者与RNA聚合酶II磷酸化及转录起始有关联。

新研究扩展了PRMT4和JMJD6靶向非组蛋白底物的清单，并揭示了除在蛋白质折叠和质量控制中的经典作用之外，HSP70蛋白在染色质水平上调控基因转录的新功能。

原文标题：Arginine methylation of HSP70 regulates retinoid acid-mediated RARβ2 GENE activation

原文摘要：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.

作者：秩名