# Quaking–cZFP609 Axis Remedies Aberrant Plasticity of Vascular Smooth Muscle Cells via Mediating Platelet‐Derived Growth Factor Receptor β Degradation

## TL;DR

A new pathway involving QKI and cZFP609 helps control abnormal changes in vascular smooth muscle cells, potentially aiding recovery from vascular injury.

## Contribution

The study identifies a novel regulatory axis (QKI–cZFP609) that mediates PDGFRβ degradation to control VSMC plasticity.

## Key findings

- SIRT1 deacetylates QKI, activating it to regulate cZFP609 production.
- cZFP609 directs PDGFRβ into endosomal/lysosomal degradation, reducing VSMC proliferation.
- Overexpression of cZFP609 reduces neointimal formation after vascular injury.

## Abstract

Vascular smooth muscle cell (VSMC) plasticity is crucial for the repair after vascular injury. However, the high plasticity of VSMCs may make them transform into pathogenic phenotypes. Here, we show that VSMCs overexpressing Sirtuin 1 (SIRT1) exhibit a reduced phenotypic plasticity in the context of platelet‐derived growth factor (PDGF)‐BB treatment. SIRT1 activated Quaking (QKI)–cZFP609 axis is involved in the plasticity regulation in the VSMCs. Mechanically, SIRT1 deacetylates K133 and K134 of QKI and mediates its activation. Activated QKI binds the QKI response elements located in the upstream and downstream of the cZFP609‐forming exons in ZFP609 pre‐mRNA to mediate cZFP609 production. Furthermore, the acetylation of QKI is increased by inhibiting SIRT1 with the selective and potent inhibitor EX527 or deletion of SIRT1, accompanied with parallel decrease in cZFP609 formation. Final, we identify that cZFP609 directs PDGF receptor (PDGFR)β sorting into endosomal/lysosomal pathway and degradation by bridging PDGFRβ and Rab7, resulted in attenuating Raf–MEK–ERK cascade activation downstream of PDGFRβ signaling. Overexpression of cZFP609 remedies aberrant plasticity and overproliferation of VSMCs, and ameliorates neointimal formation. Together, these results highlight that modulating the QKI–cZFP609 axis may help propel repair without stenosis as a therapeutic strategy in vascular injury.

QKI–cZFP609 axis damps aberrant VSMC plasticity and mitigates vascular remodeling via directing PDGFRβ into endosomal/lysosomal degradation.