The E3 ubiquitin ligase Nedd4L preserves skeletal muscle stem cell quiescence by inhibiting their activation,iScience

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The E3 ubiquitin ligase Nedd4L preserves skeletal muscle stem cell quiescence by inhibiting their activation
iScience ( IF 4.6 ) Pub Date : 2024-06-11 , DOI: 10.1016/j.isci.2024.110241
Darren M Blackburn _{1,

2} , Korin Sahinyan _{1,

2} , Aldo Hernández-Corchado ₁ , Felicia Lazure _{1,

2} , Vincent Richard ₃ , Laura Raco ₂ , Gabrielle Perron ₁ , René P Zahedi _{3,

4,

5,

6} , Christoph H Borchers _{3,

7,

8,

9} , Christoph Lepper ₁₀ , Hiroshi Kawabe ₁₁ , Arezu Jahani-Asl ₁₂ , Hamed S Najafabadi ₁ , Vahab D Soleimani _{1,

2,

13}

Affiliation

Department of Human Genetics, McGill University, 3640 rue University, Montréal, QC H3A 0C7, Canada.
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte- Sainte-Catherine, Montréal, QC H3T 1E2, Canada.
Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC H3T 1E2, Canada.
Manitoba Centre for Proteomics and Systems Biology, Winnipeg, MB R3E 3P4, Canada.
Department of Internal Medicine, University of Manitoba, Winnipeg, MB R3E 3P4, Canada.
Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC H3T 1E2, Canada.
Division of Experimental Medicine, McGill University, Montréal, QC H4A 3J1, Canada.
Department of Pathology, McGill University, Montréal, QC H3A 2B4, Canada.
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine 37075 Göttingen, Germany.
Department of Cellular and Molecular Medicine and University of Ottawa Brain and Mind Research Institute, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada.
Department of Biochemistry, Microbiology & Immunology, University of Ottawa, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada.

Adult stem cells play a critical role in tissue repair and maintenance. In tissues with slow turnover, including skeletal muscle, these cells are maintained in a mitotically quiescent state yet remain poised to re-enter the cell cycle to replenish themselves and regenerate the tissue. Using a panomics approach we show that the PAX7/NEDD4L axis acts against muscle stem cell activation in homeostatic skeletal muscle. Our findings suggest that PAX7 transcriptionally activates the E3 ubiquitin ligase Nedd4L and that the conditional genetic deletion of Nedd4L impairs muscle stem cell quiescence, with an upregulation of cell cycle and myogenic differentiation genes. Loss of Nedd4L in muscle stem cells results in the expression of doublecortin (DCX), which is exclusively expressed during their in vivo activation. Together, these data establish that the ubiquitin proteasome system, mediated by Nedd4L, is a key contributor to the muscle stem cell quiescent state in adult mice.

中文翻译：

E3 泛素连接酶 Nedd4L 通过抑制骨骼肌干细胞的激活来保持骨骼肌干细胞的静止状态

成体干细胞在组织修复和维护中起着关键作用。在更新缓慢的组织（包括骨骼肌）中，这些细胞维持在有丝分裂静止状态，但仍准备重新进入细胞周期以补充自身并再生组织。使用泛组学方法，我们表明 PAX7/NEDD4L 轴对稳态骨骼肌中的肌肉干细胞激活起作用。我们的研究结果表明，PAX7 转录激活 E3 泛素连接酶 Nedd4L，并且 Nedd4L 的条件性基因缺失会损害肌肉干细胞静止，从而上调细胞周期和肌原分化基因。肌肉干细胞中 Nedd4L 的缺失导致双皮质素（DCX）的表达，该蛋白仅在其体内激活期间表达。总之，这些数据确定了由 Nedd4L 介导的泛素蛋白酶体系统是成年小鼠肌肉干细胞静止状态的关键贡献者。

更新日期：2024-06-11

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