WSTF nuclear autophagy regulates chronic but not acute inflammation

• 成果类型: Article
• 署名作者: Wang, Yu; Eapen, Vinay V.; Liang, Yaosi; Kournoutis, Athanasios; Sherman, Marc Samuel; Xu, Yanxin; Onorati, Angelique; Li, Xianting; Zhou, Xiaoting; Corey, Kathleen E.; Du, Kuo; Cabral Burkard, Ana Maria; Ho, Chia-Kang; Xie, Jing; Zhang, Hui; Maeso-Diaz, Raquel; Ma, Xinyi; Rieprecht, Ulrike; O'Brien, Tara; Cetinbas, Murat; Wang, Lu; Liu, Jihe; Bretz, Corey; Havas, Aaron P.; Zhou, Zhuo; Ho Sui, Shannan J.; Saladi, Srinivas Vinod; Sadreyev, Ruslan I.; Adams, Peter D.; Kingston, Robert E.; Diehl, Anna Mae; Alman, Benjamin; Goessling, Wolfram; Yue, Zhenyu; Wang, Xiao-Fan; Johansen, Terje; Dou, Zhixun
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; UiT The Arctic University of Tromso; Harvard University; Harvard Medical School; Duke University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Duke University; Shanghai Jiao Tong University; Duke University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; University of Texas System; University of Texas at San Antonio; Harvard University; Harvard T.H. Chan School of Public Health; Sanford Burnham Prebys Medical Discovery Institute; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; University System of Ohio; University of Toledo; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2977
• DOI: 10.1038/s41586-025-09234-1
• 发表日期: 2025-08-21
• 关键词: differential expression; systematic optimization; endoplasmic-reticulum; protein expression; mass-spectrometry; receptor binding; human brain; web server; senescence; chromatin

摘要

Acute inflammation is an essential response that our bodies use to combat infections1. However, in the absence of infections, chronic inflammation can have a pivotal role in the onset and progression of chronic diseases, such as arthritis, cancer, autoimmune disorders, metabolic-dysfunction-associated steatohepatitis (MASH), and most ageing-associated pathologies2,3. The underlying mechanisms that distinguish chronic inflammation from its acute counterpart remain unclear, posing challenges to the development of targeted therapies for these major diseases. Here we identify a mechanism that separates the two responses: during chronic but not acute inflammation, chromatin remodelling is influenced by nuclear autophagy, in which the WSTF protein of the ISWI chromatin-remodelling complex interacts with the ATG8 autophagy protein family in the nucleus. This interaction leads to WSTF nuclear export and subsequent degradation by autophagosomes and lysosomes in the cytoplasm. Loss of WSTF leads to chromatin opening over inflammatory genes, amplifying inflammation. Cell-penetrating peptides that block the WSTF-ATG8 interaction do not affect acute inflammation but suppress chronic inflammation in senescence as well as in MASH and osteoarthritis in mouse models and patient samples. The ability to specifically target chronic inflammation without blunting acute inflammation offers an approach for treating common chronic inflammatory diseases.