Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan.
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan.
Int J Mol Sci. 2020 May 17;21(10):3546. doi: 10.3390/ijms21103546.
The activation of p38 mitogen-activated protein kinases (MAPKs) through a phosphorylation cascade is the canonical mode of regulation. Here, we report a novel activation mechanism for p38α. We show that Arg49 and Arg149 of p38α are methylated by protein arginine methyltransferase 1 (PRMT1). The non-methylation mutations of Lys49/Lys149 abolish the promotive effect of p38α on erythroid differentiation. MAPK kinase 3 (MKK3) is identified as the major p38α upstream kinase and MKK3-mediated activation of the R49/149K mutant p38α is greatly reduced. This is due to a profound reduction in the interaction of p38α and MKK3. PRMT1 can enhance both the methylation level of p38α and its interaction with MKK3. However, the phosphorylation of p38α by MKK3 is not a prerequisite for methylation. MAPK-activated protein kinase 2 (MAPKAPK2) is identified as a p38α downstream effector in the PRMT1-mediated promotion of erythroid differentiation. The interaction of MAPKAPK2 with p38α is also significantly reduced in the R49/149K mutant. Together, this study unveils a novel regulatory mechanism of p38α activation via protein arginine methylation on R49/R149 by PRMT1, which impacts partner interaction and thus promotes erythroid differentiation. This study provides a new insight into the complexity of the regulation of the versatile p38α signaling and suggests new directions in intervening p38α signaling.
丝裂原活化蛋白激酶（MAPKs）的激活是通过磷酸化级联反应的经典调节模式。在这里，我们报告了一种新型的 p38α 激活机制。我们表明，p38α 的 Arg49 和 Arg149 被蛋白精氨酸甲基转移酶 1（PRMT1）甲基化。p38α 的 Lys49/Lys149 非甲基化突变会消除 p38α 对红细胞分化的促进作用。MAPK 激酶 3（MKK3）被鉴定为 p38α 的主要上游激酶，并且 MKK3 介导的 R49/149K 突变 p38α 的激活大大降低。这是由于 p38α 和 MKK3 的相互作用明显减少。PRMT1 可以增强 p38α 的甲基化水平及其与 MKK3 的相互作用。然而，MKK3 对 p38α 的磷酸化不是甲基化的前提条件。MAPK 激活蛋白激酶 2（MAPKAPK2）被鉴定为 PRMT1 介导的红细胞分化促进作用中 p38α 的下游效应物。在 R49/149K 突变体中，MAPKAPK2 与 p38α 的相互作用也显著减少。总之，这项研究揭示了一种新型的 p38α 激活调节机制，即通过 PRMT1 对 R49/R149 进行蛋白精氨酸甲基化，影响伙伴相互作用，从而促进红细胞分化。这项研究为多功能 p38α 信号转导的调节复杂性提供了新的见解，并为干预 p38α 信号转导提供了新的方向。
