The 99th Annual Meeting of the Japanese Pharmacological Society

Chair:Eiichi Taira(IWATE MEDICAL UNIVERSITY)

Heart failure is a leading cause of death in developed countries. CCR4-NOT protein complex is a conserved multifaceted regulator of mRNA remodeling, which includes RNA degradation, so called deadenylation, as well as transcription and translation. The roles of mRNA remodeling in the pathology of heart failure remain elusive. We had elucidated ACE2 as a receptor for SARS-CoV and also as a protective peptidase against heart failure and acute lung injury (Nat Med 2005; Nat Commun 2020, 2021). Since ACE2 had been originally identified as a cardiac development factor in drosophila mutants, that motivated us to conduct a large-scale drosophila RNAi screening in vivo to search for genes important for cardiac stress resilience. As a result, we identified CCR4-NOT complex as a regulator of heart function (Cell 2010). We have elucidated that CCR4-NOT-mediated deadenylation is crucial for cardiomyocyte survival through suppression of Atg7 (Science Signaling 2018) also for maintaining cardiac energy homeostasis. CNOT6L deadenylase subunit regulates fibroblast-specific mRNA deadenylation of Tenascin-C upon pressure overload stress (JPET 2025). CNOT4, a temporal interactor of the complex, protects from several cardiac pathogenic conditions and also promotes cell differentiation into adipocytes through transcriptional regulation (PLoS One 2025). Human CNOTs have been recently implicated in suppression of retrotransposon-derived non-coding RNAs, and de novo mutations of human CNOTs genes cause various forms of developmental disorder. It is thus suggested that CCR4-NOT-mediated RNA remodeling is important for resilience to cardiac stress as well as maintenance of life-long whole-body homeostasis, implicating future potential therapeutic application.