FXR1 regulates vascular smooth muscle cell cytoskeleton, VSMC contractility, and blood pressure by multiple mechanisms

Amanda St. Paul, Cali Corbett, Amanda Peluzzo, Sheri Kelemen, Rachael Okune, Dale S. Haines, Kyle Preston, Satoru Eguchi, Michael V. Autieri

Research output: Contribution to journalArticlepeer-review

Abstract

Appropriate cytoskeletal organization is essential for vascular smooth muscle cell (VSMC) conditions such as hypertension. This study identifies FXR1 as a key protein linking cytoskeletal dynamics with mRNA stability. RNA immunoprecipitation sequencing (RIP-seq) in human VSMCs identifies that FXR1 binds to mRNA associated with cytoskeletal dynamics, and FXR1 depletion decreases their mRNA stability. FXR1 binds and regulates actin polymerization. Mass spectrometry identifies that FXR1 interacts with cytoskeletal proteins, particularly Arp2, a protein crucial for VSMC contraction, and CYFIP1, a WASP family verprolin-homologous protein (WAVE) regulatory complex (WRC) protein that links mRNA processing with actin polymerization. Depletion of FXR1 decreases the cytoskeletal processes of adhesion, migration, contraction, and GTPase activation. Using telemetry, conditional FXR1SMC/SMC mice have decreased blood pressure and an abundance of cytoskeletal-associated transcripts. This indicates that FXR1 is a muscle-enhanced WRC modulatory protein that regulates VSMC cytoskeletal dynamics by regulation of cytoskeletal mRNA stability and actin polymerization and cytoskeletal protein-protein interactions, which can regulate blood pressure.

Original languageEnglish
Article number112381
Pages (from-to)112381
JournalCell Reports
Volume42
Issue number4
DOIs
StatePublished - Apr 25 2023

Keywords

  • CP: Cell biology
  • WRC proteins
  • blood pressure
  • cytoskeletal
  • mRNA stability
  • vascular smooth muscle cell

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