Littlejohn Rodney, Zambrano-Carrasco Josue, Zou Jianqiu, Lu Yi, Liu Elise, Kim Il-Man, Jiao Kai, Weintraub Neal L, Zhou Jiliang, Li Jie, Su Huabo
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
Center for Biotechnology & Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
FASEB J. 2024 Dec 13;38(24):e70260. doi: 10.1096/fj.202401380R.
Neddylation is a highly conserved post-translational modification that plays critical roles in various cellular processes through the modulation of cullins and non-cullin substrates. While neddylation is known to be essential for embryonic development, tumor growth, and organogenesis of different tissues, its role in cardiogenesis remains unexplored. Here, we investigated the role of neddylation in early cardiac development by deleting the gene encoding a regulatory subunit of the NEDD8-specific E1 activating enzyme, Nae1, globally and in a heart-specific fashion via Nkx2-5. Global deletion of Nae1 in mice led to embryonic lethality before embryonic day (E) 8.5, whereas cardiac-specific NAE1 knockout mice died at around E12.5 with pronounced cardiac effusion and peripheral hemorrhage, characteristic of cardiac failure. Histological analysis revealed significant thinning of the compact myocardium and reduced trabeculae in mutant hearts, which were accompanied by reduced cardiomyocyte proliferation. Unbiased transcriptomic analysis identified perturbations in cardiomyocyte proliferation and myofibril architecture in mutant hearts. Subsequent analysis showed that loss of NAE1 disrupted sarcomere assembly dysregulated the expression of several important contractile proteins, and impaired mitochondrial function in the developing heart, which was accompanied by downregulation of key cardiac transcription factors including NKX2-5 and SRF. Collectively, our findings demonstrate the essential role of neddylation in cardiogenesis at least in part by driving cardiomyocyte proliferation and myofibrillogenesis.
Neddylation是一种高度保守的翻译后修饰，通过调节cullins和非cullin底物在各种细胞过程中发挥关键作用。虽然已知Neddylation对胚胎发育、肿瘤生长和不同组织的器官发生至关重要，但其在心脏发生中的作用仍未被探索。在这里，我们通过在整体水平以及通过Nkx2-5以心脏特异性方式删除编码NEDD8特异性E1激活酶Nae1的调节亚基的基因，研究了Neddylation在早期心脏发育中的作用。在小鼠中整体删除Nae1导致在胚胎第（E）8.5天之前胚胎致死，而心脏特异性NAE1基因敲除小鼠在E12.5左右死亡，伴有明显的心包积液和外周出血，这是心力衰竭的特征。组织学分析显示突变心脏中致密心肌显著变薄且小梁减少，同时伴有心肌细胞增殖减少。无偏转录组分析确定了突变心脏中心肌细胞增殖和肌原纤维结构的扰动。随后的分析表明，NAE1的缺失破坏了肌节组装，使几种重要收缩蛋白的表达失调，并损害了发育中心脏的线粒体功能，同时伴有包括NKX2-5和SRF在内的关键心脏转录因子的下调。总的来说，我们的研究结果表明Neddylation在心脏发生中至少部分通过驱动心肌细胞增殖和肌原纤维形成发挥重要作用。
