HEATR3 recognizes membrane rupture and facilitates xenophagy in response to Salmonella invasion

• 成果类型: Article
• 署名作者: Arakawa, Masashi; Uriu, Keiya; Saito, Koki; Hirose, Mai; Katoh, Kaoru; Asano, Krisana; Nakane, Akio; Saitoh, Tatsuya; Yoshimori, Tamotsu; Morita, Eiji
• 署名单位: Hirosaki University; National Institute of Advanced Industrial Science & Technology (AIST); Hirosaki University; University of Osaka; University of Osaka; University of Osaka; University of Osaka
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12929
• DOI: 10.1073/pnas.2420544122
• 发表日期: 2025-04-08
• 关键词: genome-wide association; leucine methyl-ester; damaged lysosomes; nuclear import; crohn-disease; autophagy; cells; degradation; biogenesis; clearance

摘要

Bacterial invasion into the cytoplasm of epithelial cells triggers the activation of the cellular autophagic machinery as a defense mechanism, a process known as xenophagy. In as a factor involved in this defense mechanism using quantitative mass spectrometry promotes Salmonella proliferation in the cytoplasm. HEATR3 also localizes to lysosomes damaged by chemical treatment, suggesting that Salmonella recognition is facilitated by damage to the host cell membrane. HEATR3 deficiency impairs LC3 recruitment to damaged membranes and blocks the delivery of the target to the lysosome. These phenotypes were rescued by exogenous expression of wild- type HEATR3 but not by the LIR mutant, indicating the crucial role of the HEATR3-LC3 interaction in the receptor for selective autophagy. HEATR3 is delivered to lysosomes in an autophagy- dependent manner. Although HEATR3 recruitment to the damaged membrane was unaffected chelator, suggesting involvement upstream of the autophagic pathway. These findings suggest that HEATR3 serves as a receptor for selective autophagy and is able to identify damaged membranes, facilitate the removal of damaged lysosomes, and target invading bacteria within cells.