COP9 signalosome stabilized MALT1 alleviates DNA replication stress in radiation-induced lung injury

Résumé fourni par la source

Radiation-induced lung injury (RILI) is a severe complication of thoracic radiotherapy, and effective interventions are still lacking. DNA damage is a primary instigator of RILI, which triggers DNA replication stress that in turn aggravates genome instability, forming a vicious cycle. Here, using a RILI mouse model and the human bronchial epithelial cell line BEAS-2B, we identify the CSN5-MALT1 axis as a critical protective pathway against RILI by alleviating DNA replication stress. The expression of MALT1 and CSN5 were upregulated in both a RILI mouse model and irradiated BEAS-2B cells. Genetic depletion of either MALT1 or CSN5 significantly exacerbated IR-induced DNA damage and replication stress, impaired DNA repair capacity, and reduced cell survival. Mechanistically, CSN5 stabilized the MALT1 protein by reducing its ubiquitination. Rescue experiments established that CSN5 functions upstream of MALT1 to protect cells from IR-induced DNA damage by mitigating replication stress in BEAS-2B cells. Notably, all these effects were only observed upon irradiation and were absent under non-irradiated cells. Our study reveals a CSN5-MALT1 axis which is activated by IR to preserve genome integrity, highlighting a potential therapeutic strategy for RILI.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.