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Background <p>Airborne particulate matter is a major environmental risk factor for airway disease, but the early molecular events that initiate epithelial dysfunction before overt inflammation remain poorly understood. In particular, the mechanisms by which acute, non-cytotoxic particulate exposure disrupts epithelial structural organization have not been fully defined.</p> Methods <p>We used an unbiased phosphoproteomic approach to identify early signaling responses in human bronchial epithelial cells exposed to particulate matter under non-lethal conditions. Phosphatase of regenerating liver-3 (PRL-3; gene symbol PTP4A3) function was evaluated using pharmacologic inhibition and genetic suppression, with in vivo validation in a mouse acute airway exposure model. Data were analyzed using appropriate parametric or non-parametric tests, including one-way or two-way analysis of variance, and P values &lt; 0.05 were considered statistically significant.</p> Results <p>Phosphoproteomic profiling identified coordinated changes in cytoskeleton-associated proteins, including ezrin-radixin-moesin family members, suggesting early disruption of membrane-cytoskeleton coupling after particulate exposure. Acute particulate exposure induced rapid and transient upregulation and membrane relocalization of PRL-3, accompanied by PRL-3-sensitive ezrin dephosphorylation in vitro and in vivo. Pharmacological inhibition or genetic suppression of PRL-3 restored ezrin phosphorylation and attenuated epithelial–mesenchymal transition (EMT)-associated molecular changes and mucin 5AC (MUC5AC) upregulation. These effects were observed independently of protein kinase B (Akt), extracellular signal-regulated kinase (ERK), and mechanistic target of rapamycin (mTOR) signaling, and were reproducible across multiple particulate types, including urban particulate matter (UPM), diesel exhaust particles (DEP), and particulate matter with an aerodynamic diameter of ≤ 10&#xa0;μm (PM<sub>10</sub>).</p> Conclusions <p>Our findings identify a PRL-3-sensitive, cytoskeleton-centered signaling pathway as an early molecular mechanism connecting particulate exposure to molecular alterations associated with early airway epithelial responses.</p>

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PRL-3–sensitive cytoskeletal signaling mediates early airway epithelial responses to particulate matter

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月22日

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  • Hyungkyung Yoon,
  • Moonhwan Choi,
  • Youngeun Ha,
  • Jiwon An,
  • An-Soo Jang,
  • Sang-Kyung Lee,
  • Taiyoun Rhim

摘要

Background

Airborne particulate matter is a major environmental risk factor for airway disease, but the early molecular events that initiate epithelial dysfunction before overt inflammation remain poorly understood. In particular, the mechanisms by which acute, non-cytotoxic particulate exposure disrupts epithelial structural organization have not been fully defined.

Methods

We used an unbiased phosphoproteomic approach to identify early signaling responses in human bronchial epithelial cells exposed to particulate matter under non-lethal conditions. Phosphatase of regenerating liver-3 (PRL-3; gene symbol PTP4A3) function was evaluated using pharmacologic inhibition and genetic suppression, with in vivo validation in a mouse acute airway exposure model. Data were analyzed using appropriate parametric or non-parametric tests, including one-way or two-way analysis of variance, and P values < 0.05 were considered statistically significant.

Results

Phosphoproteomic profiling identified coordinated changes in cytoskeleton-associated proteins, including ezrin-radixin-moesin family members, suggesting early disruption of membrane-cytoskeleton coupling after particulate exposure. Acute particulate exposure induced rapid and transient upregulation and membrane relocalization of PRL-3, accompanied by PRL-3-sensitive ezrin dephosphorylation in vitro and in vivo. Pharmacological inhibition or genetic suppression of PRL-3 restored ezrin phosphorylation and attenuated epithelial–mesenchymal transition (EMT)-associated molecular changes and mucin 5AC (MUC5AC) upregulation. These effects were observed independently of protein kinase B (Akt), extracellular signal-regulated kinase (ERK), and mechanistic target of rapamycin (mTOR) signaling, and were reproducible across multiple particulate types, including urban particulate matter (UPM), diesel exhaust particles (DEP), and particulate matter with an aerodynamic diameter of ≤ 10 μm (PM10).

Conclusions

Our findings identify a PRL-3-sensitive, cytoskeleton-centered signaling pathway as an early molecular mechanism connecting particulate exposure to molecular alterations associated with early airway epithelial responses.