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

Author:

Chen Xianwei1,Li Yanfeng1,Xu Jin1ORCID,Cui Yong2,Wu Qian3,Yin Haidi3,Li Yuying4,Gao Chuan1,Jiang Liwen2,Wang Huating4ORCID,Wen Zilong1ORCID,Yao Zhongping3ORCID,Wu Zhenguo1ORCID

Affiliation:

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

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

3. Department of Applied Biology and Chemical Technology, the Hong Kong Polytechnic University, Hong Kong, China

4. Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, the Chinese University of Hong Kong, Hong Kong, China

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 or genetic knockout, we found that Styxl2 plays an essential role in maintaining sarcomere integrity in developing muscles of both zebrafish and mice. To further reveal the functions of Styxl2 in adult muscles, we generated two inducible knockout mouse models: one with Styxl2 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.

Publisher

eLife Sciences Publications, Ltd

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