FXR1 regulates vascular smooth muscle cell cytoskeleton, VSMC contractility, and blood pressure by multiple mechanisms
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 b...
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Published in | Cell reports (Cambridge) Vol. 42; no. 4; p. 112381 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
25.04.2023
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | 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.
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•FXR1 interacts with cytoskeletal RNAs to regulate their abundance and stability•FXR1 interacts with cytoskeletal proteins, such as WAVE proteins CYFIP1 and ARP2•FXR1 regulates cytoskeletal-dependent processes in vascular smooth muscle cells•The genetic deletion of FXR1 in smooth muscle decreases blood pressure in mice
St. Paul et al. show that FXR1 links mRNA processing with actin dynamics in vascular smooth muscle cells by binding to mRNAs and proteins that regulate the cytoskeleton. Deletion of FXR1 leads to decreased cellular migration, adhesion, and contraction. Additionally, mice without FXR1 have decreased blood pressure. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS A.S.P. performed the majority of the molecular biology, cell culture, and ex vivo experiments. A.S.P created the graphical abstract using BioRender.com. C.C. performed cell culture and ex vivo experiments. A.P. performed ex vivo experiments. S.K. and R.O. performed immunohistochemistry. D.S.H. interpreted and performed MS data. K.P. performed mouse telemetry. S.E. provided the SmMHC-CreERT2 mouse and telemetry equipment. M.V.A. designed experiments, interpreted data, performed some western blots, and wrote the majority of the manuscript. |
ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2023.112381 |