A Splicing-Independent Function of RBM10 Controls Specific 3' UTR Processing to Regulate Cardiac Hypertrophy

Cell Rep. 2018 Sep 25;24(13):3539-3553. doi: 10.1016/j.celrep.2018.08.077.

Abstract

RNA binding motif protein 10 (RBM10) is a regulator of alternative splicing in apoptosis and inflammation. We discovered a splicing-independent function of RBM10 critical for the regulation of heart failure (HF). RBM10 is enriched in the heart and associates with Star-PAP (TUT1) to control the expression and 3' end processing of cardiac mRNAs. The RBM10 RRM2 domain binds the Star-PAP catalytic domain, which directs Star-PAP activity toward polyadenylation. RBM10 binds the pre-mRNA UTR, assembles the Star-PAP complex, and guides this complex specifically to mRNAs encoding anti-hypertrophy regulators. Accordingly, we tested cellular hypertrophy in rat cardiomyoblasts and cardiac hypertrophy (CH) and the subsequent progression to HF in Wistar rat hearts. We demonstrated downregulation of RBM10 during CH and HF. Ectopic re-expression of RBM10 rescued cardiomyocyte hypertrophy. RBM10 depletion evoked a hypertrophic response in H9c2 cells. Our results establish an anti-hypertrophy mechanism mediated by RBM10 in the heart that is directly linked to HF.

Keywords: 3′ UTR; 3′ end processing; RBM10; Star-PAP; cardiac hypertrophy; cardiac mRNA; gene expression; heart failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism*
  • Down-Regulation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Male
  • Myocytes, Cardiac / metabolism
  • Nucleotidyltransferases / chemistry
  • Nucleotidyltransferases / metabolism
  • Protein Binding
  • RNA 3' End Processing*
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Rats
  • Rats, Wistar

Substances

  • RBM10 protein, human
  • RNA-Binding Proteins
  • Nucleotidyltransferases
  • TUT1 protein, human