Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan.
Nat Commun. 2022 Sep 29;13(1):5715. doi: 10.1038/s41467-022-33363-0.
Protein kinase A promotes beige adipogenesis downstream from β-adrenergic receptor signaling by phosphorylating proteins, including histone H3 lysine 9 (H3K9) demethylase JMJD1A. To ensure homeostasis, this process needs to be reversible however, this step is not well understood. We show that myosin phosphatase target subunit 1- protein phosphatase 1β (MYPT1-PP1β) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1β depletion results in JMJD1A-mediated H3K9 demethylation and activation of the Ucp1 enhancer/promoter regions. Interestingly, MYPT1-PP1β also dephosphorylates myosin light chain which regulates actomyosin tension-mediated activation of YAP/TAZ which directly stimulates Ucp1 gene expression. Pre-adipocyte specific Mypt1 deficiency increases cold tolerance with higher Ucp1 levels in subcutaneous white adipose tissues compared to control mice, confirming this regulatory mechanism in vivo. Thus, we have uncovered regulatory cross-talk involved in beige adipogenesis that coordinates epigenetic regulation with direct activation of the mechano-sensitive YAP/TAZ transcriptional co-activators.
蛋白激酶 A (PKA) 通过磷酸化包括组蛋白 H3 赖氨酸 9 (H3K9) 去甲基酶 JMJD1A 在内的多种蛋白，促进β肾上腺素能受体信号下游的米色脂肪生成。为了确保体内平衡，这个过程需要是可逆的，但这一步骤还不是很清楚。我们发现肌球蛋白磷酸酶靶亚单位 1-蛋白磷酸酶 1β (MYPT1-PP1β) 的磷酸酶活性被 PKA 依赖性磷酸化抑制，这增加了磷酸化的 JMJD1A 和米色脂肪生成。从机制上讲，MYPT1-PP1β 的耗竭导致 JMJD1A 介导的 H3K9 去甲基化和 Ucp1 增强子/启动子区域的激活。有趣的是，MYPT1-PP1β 还去磷酸化肌球蛋白轻链，后者调节肌动球蛋白张力介导的 YAP/TAZ 的激活，而 YAP/TAZ 直接刺激 Ucp1 基因表达。与对照小鼠相比，前脂肪细胞特异性 Mypt1 缺失增加了冷耐受性，皮下白色脂肪组织中的 Ucp1 水平更高，这在体内证实了这种调节机制。因此，我们揭示了米色脂肪生成中涉及的调节交叉对话，该对话协调了表观遗传调控与机械敏感的 YAP/TAZ 转录共激活因子的直接激活。
