Anti-fibrotic effects of mRNA deadenylase CNOT6L in the pathogenesis of heart failure

Abstract

Heart failure is a leading cause of death in developed countries. The role of mRNA regulation in the pathology of heart failure remains elusive. CCR4-NOT complex is a multi-subunit protein complex constituting exonuclease-mediated degradation of mRNA’s poly(A) tails, a process called deadenylation. Here we analyzed the roles of deadenylase subunit in heart failure. After 2 weeks of transverse aortic constriction (TAC)-induced pressure overload, expression of CNOT6L deadenylase subunit was markedly upregulated in the hearts. Loss of CNOT6L significantly decreased cardiac contractility and enhanced fibrosis at 2 weeks after TAC. Transcriptome analyses elucidated that CNOT6L targets mRNA of the GeneX, which stimulates tissue fibrosis. Furthermore, CNOT6L markedly suppressed geneX expression in cardiac fibroblasts. Poly(A) tail length and luciferase reporter analyses revealed that CNOT6L regulates deadenylation via the cis-element in the geneX 3'UTR. Double knockout of GeneX and CNOT6L improved cardiac fibrosis and dysfunction in single CNOT6 knockout mice. Thus, CNOT6L deadenylase prevents the progression of heart failure by suppressing the expression of fibrotic geneX in cardiac fibroblasts, implicating a potential therapeutic strategy of targeting mRNA deadenylation.