Department of Biochemistry, School of Biological Sciences, Chungbuk National University, Cheongju, 28644, Republic of Korea.
Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600025, India.
Cell Death Dis. 2018 May 1;9(5):471. doi: 10.1038/s41419-018-0489-x.
Smad proteins have been implicated in metabolic processes, but little is known about how they regulate metabolism. Because Smad 2, 3, 4, and 7 have previously been shown to interact with murine protein serine-threonine kinase 38 (MPK38), an AMP-activated protein kinase (AMPK)-related kinase that has been implicated in obesity-associated metabolic defects, we investigated whether Smad proteins regulate metabolic processes via MPK38. Smads2/3/4 increased, but Smad7 decreased, MPK38-mediated apoptosis signal-regulating kinase-1 (ASK1)/transforming growth factor-β (TGF-β)/p53 signaling. However, MPK38-mediated phosphorylation-defective Smad mutants (Smad2 S245A, Smad3 S204A, Smad4 S343A, and Smad7 T96A) had no such effect. In addition, Smads2/3/4 increased, but Smad7 decreased, the stability of MPK38. Consistent with this, Smads2/3/4 attenuated complex formation between MPK38 and its negative regulator thioredoxin (Trx), whereas Smad7 increased this complex formation. However, an opposite effect was observed on complex formation between MPK38 and its positive regulator zinc-finger-like protein 9 (ZPR9). When Smads were overexpressed in high-fat diet (HFD)-fed obese mice using an adenoviral delivery system, Smads2/3/4 improved, but Smad7 worsened, obesity-associated metabolic parameters and inflammation in a MPK38 phosphorylation-dependent manner. These findings suggest that Smad proteins have class-specific impacts on obesity-associated metabolism by differentially regulating MPK38 activity in diet-induced obese mice.
Smad 蛋白已被牵涉到代谢过程中，但关于它们如何调节代谢的知之甚少。因为 Smad2、3、4 和 7 先前已被证明与鼠蛋白丝氨酸-苏氨酸激酶 38（MPK38）相互作用，MPK38 是一种与肥胖相关代谢缺陷有关的 AMP 激活蛋白激酶（AMPK）相关激酶，我们研究了 Smad 蛋白是否通过 MPK38 调节代谢过程。Smads2/3/4 增加，但 Smad7 减少，MPK38 介导的凋亡信号调节激酶 1（ASK1）/转化生长因子-β（TGF-β）/p53 信号。然而，MPK38 介导的磷酸化缺陷 Smad 突变体（Smad2 S245A、Smad3 S204A、Smad4 S343A 和 Smad7 T96A）没有这种作用。此外，Smads2/3/4 增加，但 Smad7 减少，MPK38 的稳定性。与之一致的是，Smads2/3/4 减弱了 MPK38 与其负调节剂硫氧还蛋白（Trx）之间的复合物形成，而 Smad7 增加了这种复合物形成。然而，在 MPK38 与其正调节剂锌指样蛋白 9（ZPR9）之间的复合物形成上观察到相反的效果。当使用腺病毒传递系统在高脂肪饮食（HFD）喂养的肥胖小鼠中过表达 Smads 时，Smads2/3/4 改善了肥胖相关的代谢参数和炎症，而 Smad7 则恶化了肥胖相关的代谢参数和炎症，这是一种依赖于 MPK38 磷酸化的方式。这些发现表明，Smad 蛋白通过在饮食诱导的肥胖小鼠中差异调节 MPK38 活性，对肥胖相关的代谢具有特定的影响。
