# ARPC2 Promotes Pulmonary Fibrosis by Regulating MRTFA Activity Independent of the Canonical ARP2/3 Complex

## TL;DR

ARPC2 promotes lung fibrosis by controlling MRTFA activity, offering a new target for treating idiopathic pulmonary fibrosis.

## Contribution

ARPC2's role in fibrosis is identified independently of the ARP2/3 complex, revealing a novel mechanism in lung disease progression.

## Key findings

- ARPC2 modulates profibrotic gene expression and MRTFA nuclear localization in lung fibroblasts.
- ARPC2 and MRTFA co-regulate specific fibrotic genes during fibroblast-to-myofibroblast transition.
- ARPC2 influences TGF-β1-dependent MRTFA/G-actin complex formation, distinct from ARP2/3 complex functions.

## Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by the pathological accumulation of collagen-rich extracellular matrix, resulting in irreversible lung remodeling and respiratory failure. The incomplete understanding of IPF pathogenesis has hindered the development of effective therapeutics. Here, we investigate the mechanism by which the actin-related protein 2/3 complex subunit 2 (ARPC2) contributes to the fibrotic response in lung fibroblasts. Modulating of ARPC2 expression levels altered the expression of profibrotic genes, including α-smooth muscle actin (ACTA2), in TGF-β1-treated MRC-5 cells at the transcriptional level. We further show that ARPC2 regulates the TGF-β1-mediated nuclear translocation of myocardin-related transcription factor-A (MRTFA), a central driver of fibrotic gene induction. Our data indicate that ARPC2 plays a distinct role in profibrotic gene expression and MRTFA nuclear localization, distinguishing its function from other components of the actin-related protein 2/3 (ARP2/3) complex. Furthermore, ARPC2 appears to modulate the TGF-β1-dependent formation of MRTFA/G-actin complexes. Finally, transcriptomic analysis of cells depleted of ARPC2, ACTR2, or MRTFA revealed that ARPC2 and MRTFA co-regulate a specific repertoire of fibrotic genes. These observations support a profibrotic function for ARPC2 during fibroblast-to-myofibroblast transition (FMT), highlighting it as a potential therapeutic target for IPF.