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Stxyl2 通过与非肌肉肌球蛋白 IIs 结合并促进其降解来调节新的肌节组装。

Styxl2 regulates de novo sarcomere assembly by binding to non-muscle myosin IIs and promoting their degradation.

机构信息

Division of Life Science, Hong Kong University of Science & Technology, Hong Kong, China.

School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China.

出版信息

Elife. 2024 Jun 3;12:RP87434. doi: 10.7554/eLife.87434.

DOI:10.7554/eLife.87434
PMID:38829202
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11147509/
Abstract

Styxl2, a poorly characterized pseudophosphatase, was identified as a transcriptional target of the Jak1-Stat1 pathway during myoblast differentiation in culture. Styxl2 is specifically expressed in vertebrate striated muscles. By gene knockdown in zebrafish or genetic knockout in mice, we found that Styxl2 plays an essential role in maintaining sarcomere integrity in developing muscles. To further reveal the functions of Styxl2 in adult muscles, we generated two inducible knockout mouse models: one with being deleted in mature myofibers to assess its role in sarcomere maintenance, and the other in adult muscle satellite cells (MuSCs) to assess its role in de novo sarcomere assembly. We find that Styxl2 is not required for sarcomere maintenance but functions in de novo sarcomere assembly during injury-induced muscle regeneration. Mechanistically, Styxl2 interacts with non-muscle myosin IIs, enhances their ubiquitination, and targets them for autophagy-dependent degradation. Without Styxl2, the degradation of non-muscle myosin IIs is delayed, which leads to defective sarcomere assembly and force generation. Thus, Styxl2 promotes de novo sarcomere assembly by interacting with non-muscle myosin IIs and facilitating their autophagic degradation.

摘要

Styxl2 是一种特征不明显的假磷酸酶，在培养中的成肌细胞分化过程中，被鉴定为 Jak1-Stat1 通路的转录靶标。Styxl2 特异性表达于脊椎动物的横纹肌中。通过在斑马鱼中进行基因敲低或在小鼠中进行基因敲除，我们发现 Styxl2 在维持发育中肌肉的肌节完整性方面发挥着重要作用。为了进一步揭示 Styxl2 在成年肌肉中的功能，我们构建了两种可诱导的敲除小鼠模型：一种是在成熟肌纤维中敲除 ，以评估其在肌节维持中的作用；另一种是在成年肌肉卫星细胞（MuSCs）中敲除 ，以评估其在新肌节组装中的作用。我们发现 Styxl2 对于肌节维持不是必需的，但在损伤诱导的肌肉再生过程中，它在新肌节组装中发挥作用。在机制上，Styxl2 与非肌肉肌球蛋白 IIs 相互作用，增强其泛素化，并将其靶向自噬依赖性降解。没有 Styxl2，非肌肉肌球蛋白 IIs 的降解会被延迟，导致肌节组装和力产生缺陷。因此，Styxl2 通过与非肌肉肌球蛋白 IIs 相互作用并促进其自噬降解，从而促进新的肌节组装。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ae8/11147509/85747b3878d8/elife-87434-sa4-fig3.jpg
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