PRMT5 mediates FoxO1 methylation and subcellular localization to regulate lipophagy in myogenic progenitors.
PRMT5 mediates FoxO1 methylation and subcellular localization to regulate lipophagy in myogenic progenitors.
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DOI：
10.1016/j.celrep.2023.113329
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发表时间：
2023-11-28
期刊：
影响因子：
8.8
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中科院分区：
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发育受多种因素调节，包括蛋白质甲基化状态。虽然PRMT 5因其通过介导精氨酸的对称二甲基化在肿瘤发生中的作用而闻名，但其在正常发育中的作用仍然难以捉摸。使用Myod 1Cre驱动胚胎成肌细胞中的Prmt 5敲除（Prmt 5 MKO），我们剖析了PRMT 5在肌发生中的作用。Prmt 5 MKO小鼠正常出生，但表现出进行性肌肉萎缩和过早死亡。Prmt 5 MKO抑制增殖并促进胚胎成肌细胞的过早分化，减少出生后小鼠中卫星细胞的数量和再生功能。从机制上讲，PRMT 5甲基化并使FoxO 1不稳定。Prmt 5 MKO增加总FoxO 1水平并促进其细胞质积累，导致自噬激活和脂滴（LD）消耗。全身抑制Prmt 5 MKO小鼠中的自噬恢复成肌细胞中的LD并适度改善肌肉再生。总之，PRMT 5至少部分通过介导FoxO 1甲基化和LD周转对肌肉发育和再生至关重要。Kim等人使用敲除（KO）小鼠报道了PRMT 5在肌肉发育中的作用。成肌细胞特异性Prmt 5-KO损害肌生成并导致过早死亡。PRMT 5调节FoxO 1的亚细胞定位，其影响脂滴的自噬。这项工作揭示了PRMT 5，FoxO 1和肌肉发育所必需的脂肪吞噬之间的相互作用。
Development is regulated by various factors, including protein methylation status. While PRMT5 is well known for its roles in oncogenesis by mediating symmetric di-methylation of arginine, its role in normal development remains elusive. Using Myod1Cre to drive Prmt5 knockout in embryonic myoblasts (Prmt5MKO), we dissected the role of PRMT5 in myogenesis. The Prmt5MKO mice are born normally but exhibit progressive muscle atrophy and premature death. Prmt5MKO inhibits proliferation and promotes premature differentiation of embryonic myoblasts, reducing the number and regenerative function of satellite cells in postnatal mice. Mechanistically, PRMT5 methylates and destabilizes FoxO1. Prmt5MKO increases the total FoxO1 level and promotes its cytoplasmic accumulation, leading to activation of autophagy and depletion of lipid droplets (LDs). Systemic inhibition of autophagy in Prmt5MKO mice restores LDs in myoblasts and moderately improves muscle regeneration. Together, PRMT5 is essential for muscle development and regeneration at least partially through mediating FoxO1 methylation and LD turnover. Kim et al. report the role of PRMT5 in muscle development using knockout (KO) mice. Myoblast-specific Prmt5-KO impairs myogenesis and causes premature death. PRMT5 regulates subcellular localization of FoxO1, which influences autophagy of lipid droplets. The work uncovers an interplay between PRMT5, FoxO1, and lipophagy essential for muscle development.