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

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 ( Trail ^f/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.