Hsp70 Interacts with Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 To Regulate p38MAPK Stability and Myoblast Differentiation during Skeletal Muscle Regeneration
Hsp70 Interacts with Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 To Regulate p38MAPK Stability and Myoblast Differentiation during Skeletal Muscle Regeneration
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Hsp70 与丝裂原激活蛋白激酶 (MAPK) 激活蛋白激酶 2 相互作用，调节骨骼肌再生过程中 p38MAPK 的稳定性和成肌细胞分化
DOI：
10.1128/mcb.00211-18
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发表时间：
2018-12-01
影响因子：
5.3
通讯作者：
Zhou, Yi Ting
中科院分区：
文献类型：
--
作者：
Fan, Wei;Gao, Xiu Kui;Zhou, Yi Ting
损伤肌肉的再生过程依赖于肌肉干细胞来源的成肌细胞的融合和分化。热休克蛋白70对维持骨骼肌的稳态和再生非常重要，但其确切的细胞机制仍不清楚。肌肉损伤后的再生过程依赖于肌肉干细胞来源的成肌细胞的融合和分化。热休克蛋白70对维持骨骼肌的稳态和再生非常重要，但其确切的细胞机制仍不清楚。在这项研究中，我们发现热休克蛋白70在成肌细胞分化过程中上调。Hsp 70/Hsc 70的耗尽或抑制损害成肌细胞分化。重要的是，p38丝裂原活化蛋白激酶α（p38 MAPK α）而不是AKT 1的过表达挽救了Hsp 70或Hsc 70缺失的成肌细胞中肌源性分化的损伤。Hsp 70与p38 MAPK的底物MK2相互作用，调节p38 MAPK的稳定性。Hsp 70的敲低也导致完整肌肉和心脏毒素诱导的肌肉再生过程中MK2和p38 MAPK的下调。Hsp 70与MK2结合，调节成肌细胞中MK2-p38 MAPK相互作用。我们随后确定了Hsp 70-MK2相互作用所需的关键区域。功能分析表明，MK 2是必不可少的成肌细胞分化和骨骼肌再生。综上所述，我们的研究结果揭示了Hsp 70通过与MK 2相互作用稳定p38 MAPK在调节成肌细胞分化中的新作用。
The regenerative process of injured muscle is dependent on the fusion and differentiation of myoblasts derived from muscle stem cells. Hsp70 is important for maintaining skeletal muscle homeostasis and regeneration, but the precise cellular mechanism remains elusive. ABSTRACT The regenerative process of injured muscle is dependent on the fusion and differentiation of myoblasts derived from muscle stem cells. Hsp70 is important for maintaining skeletal muscle homeostasis and regeneration, but the precise cellular mechanism remains elusive. In this study, we found that Hsp70 was upregulated during myoblast differentiation. Depletion or inhibition of Hsp70/Hsc70 impaired myoblast differentiation. Importantly, overexpression of p38 mitogen-activated protein kinase α (p38MAPKα) but not AKT1 rescued the impairment of myogenic differentiation in Hsp70- or Hsc70-depleted myoblasts. Moreover, Hsp70 interacted with MK2, a substrate of p38MAPK, to regulate the stability of p38MAPK. Knockdown of Hsp70 also led to downregulation of both MK2 and p38MAPK in intact muscles and during cardiotoxin-induced muscle regeneration. Hsp70 bound MK2 to regulate MK2-p38MAPK interaction in myoblasts. We subsequently identified the essential regions required for Hsp70-MK2 interaction. Functional analyses showed that MK2 is essential for both myoblast differentiation and skeletal muscle regeneration. Taken together, our findings reveal a novel role of Hsp70 in regulating myoblast differentiation by interacting with MK2 to stabilize p38MAPK.