# TMEM131‐Mediated Soluble TRAIL Triggered Type II Alveolar Epithelial Cell Senescence in Radiation‐Induced Lung Injury

## TL;DR

This study identifies how TRAIL, a protein involved in cell death, contributes to lung injury from radiation by causing cell senescence in the lungs.

## Contribution

The study reveals that TMEM131 facilitates TRAIL secretion, which inhibits mitophagy and induces senescence in alveolar epithelial cells during radiation-induced lung injury.

## Key findings

- TRAIL is significantly increased in RILI patients and contributes to cellular senescence in type II alveolar epithelial cells.
- TMEM131 mediates TRAIL secretion by recruiting the COPII complex, impacting mitophagy and cell senescence.
- Blocking TRAIL transportation reduces cellular senescence and mitigates RILI in mice.

## Abstract

Radiation‐induced lung injury (RILI) limits radiotherapy dose for thoracic tumors. It is currently urgent to clarify RILI pathogenesis and find safe and effective therapeutical strategy. Transcriptomics of RILI mouse lungs indicate that cellular senescence is substantially involved in RILI pathogenesis, and anti‐senescence compounds alleviate RILI and pulmonary inflammatory. Single‐cell RNA sequencing and multi‐color immunofluorescence demonstrate that type II alveolar epithelial cells (AECIIs) are the main senescent cells, and quantitative proteomics illustrate that tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is more secreted. Clinical samples also confirms that the plasma levels of TRAIL are significantly increased in RILI patients. Mechanistically, AECII‐specific TRAIL knockout (Trailf/f;Sftpc‐Cre) mice presents reduced cellular senescence and RILI, accompanied by reduced mitophagy. Soluble TRAIL activates the mTOR pathway through death receptor 5 to hinder mitophagy, resulting in impaired mitochondrial accumulation and cellular senescence. Immunoprecipitation mass spectrometry identifies that endoplasmic reticulum (ER)‐localized transmembrane molecule TMEM131 interact with TRAIL and mediates its transportation from ER to Golgi through Sec23 homolog A of the coat protein complex II. Interruption of this transportation process led to ER‐associated degradation of TRAIL proteins through ubiquitylation. The results indicate the pro‐senescent role of TRAIL during RILI pathogenesis and reveals the TMEM131‐mediated intricate secretory process of TRAIL.

TMEM131 recruits the COPII complex to accelerate TRAIL transportation from endoplasmic reticulum to Golgi apparatus, and promotes soluble TRAIL secretion. TRAIL inhibits mitophagy and induces senescence through DR5 receptor in type II alveolar epithelial cells, ultimately driving radiation‐induced lung injury (RILI) progression. This study reveals TRAIL's key role in mitophagy and cellular senescence, offering a potential therapeutic target for RILI.