Neddylation drives myofibrillogenesis in the developing heart

• Published in: The FASEB journal 2024-12, Vol.38 (24), p.e70260-n/a
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; cardiac development; Cell Proliferation; Female; Gene Expression Regulation, Developmental; Heart - embryology; Heart - growth & development; Mice; Mice, Knockout; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; myofibril assembly; Myofibrils - metabolism; Myofibrils - pathology; NAE1; NEDD8 Protein - genetics; NEDD8 Protein - metabolism; Neddylation; Organogenesis; Protein Processing, Post-Translational; Ubiquitin-Activating Enzymes - genetics; Ubiquitin-Activating Enzymes - metabolism
• ISSN: 0892-6638; 1530-6860; 1530-6860
• 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 Nkx2‐5Cre. 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. We investigated how neddylation regulates early cardiogenesis by deleting Nae1, the gene encoding the regulatory subunit of NEDD8 E1 activating enzyme in the heart. Cardiac‐specific knockout of NAE1 via Nkx2‐5Cre caused cardiomyocyte proliferation arrest, metabolic impairment, and ventricular hypoplasia, culminating in cardiac failure and embryonic lethality. Our data allow us to propose that neddylation drives the expression of sarcomeric genes to promote myofibril assembly and ensures cardiogenesis by regulating the activity of NKX2‐5 and SRF.