PRRC2在eIF3调控的翻译过程中的分子机制及其对肌肉健康的影响

肌肉疾病影响肌肉系统及多个器官的正常功能，严重损害患者生活质量。申请人首次发现翻译起始因子eIF3调控早期翻译延长，影响肌肉功能，但具体分子机制尚不清楚。初步研究鉴定PRRC2为eIF3高度相互作用蛋白，最新研究结果表明PRRC2缺失导致小鼠抓力降低影响肌肉功能，PRRC2为应激颗粒形成关键蛋白且翻译可在应激颗粒中进行。分析得PRRC2结合mRNA及应激颗粒富集mRNA与eIF3选择调控mRNA有显著性交集。因此推测，PRRC2直接结合eIF3依赖mRNA将其靶向应激颗粒调控翻译过程并影响肌肉功能。本项目拟构建PRRC2条件性敲除细胞模型，研究PRRC2与eIF3依赖mRNA的关系及PRRC2相关应激颗粒在eIF3调控翻译中的作用，进一步用eIF3e敲除小鼠模型，初步探讨PRRC2对eIF3缺陷导致的肌肉疾病的影响。此项目将深入挖掘eIF3调控翻译过程的分子机制，为治疗肌肉疾病提供新思路。

Muscle diseases affect the normal function of the muscle system and multiple organs, and seriously impair the quality of patients’ life. We firstly found that translation initiation factor eIF3 could selectively regulate early translation elongation and affect muscle function, but the specific molecular mechanism remains unclear. Preliminary study results identified PRRC2 as highly interacting protein of eIF3. Combined with the latest research result, PRRC2 deficient mice affect muscle function which showed in the decrease of grip strength, in addition, PRRC2 is known to be a key protein in the formation of stress granule, and translation can be carried out in stress granule. Meanwhile, PRRC2-binding mRNA and stress granule-enriched mRNA have significant overlap with eIF3 selective-regulated mRNA. Therefore, we speculated that PRRC2 can directly bind eIF3-dependent mRNA and target to stress granule to regulate the translation process and affect muscle function. This project intends to construct PRRC2 conditional knockout cell model, in order to study the relationship between PRRC2 and eIF3-dependent mRNA and the role of PRRC2 related stress granule in eIF3 selective regulated translation. Furthermore, using eIF3e-knockout mice model to preliminary study the effect of PRRC2 on muscle disease caused by eIF3 defects. This project will further explore the molecular mechanism of translation process regulated by eIF3 and provide new ideas for the treatment of muscle diseases.