WSTF nuclear autophagy regulates chronic but not acute inflammation
Open accessPublished version of a preprint
Abstract
Acute inflammation is an essential response that our bodies use to combat infections 1. 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 pathologies 2,3. 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.
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- Authors
- Wang, Y., Eapen, V. V., Liang, Y., Kournoutis, A., Sherman, M. S., Xu, Y., Onorati, A., Li, X., Zhou, X., Corey, K. E., Du, K., Cabral Burkard, A. M., Ho, C.-K., Xie, J., Zhang, H., Maeso-Díaz, R., Ma, X., Rieprecht, U., O’Brien, T., Cetinbas, M., Wang, L., Liu, J., Bretz, C., Havas, A. P., Zhou, Z., Ho Sui, S. J., Saladi, S. V., Sadreyev, R. I., Adams, P. D., Kingston, R. E., Diehl, A. M., Alman, B., Goessling, W., Yue, Z., Wang, X.-F., Johansen, T., & Dou, Z.
- Affiliations
- Harvard University (US)
- UiT The Arctic University of Norway (NO)
- Icahn School of Medicine at Mount Sinai (US)
- Duke University (US)
- The University of Texas at San Antonio Health Science Center (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- University of Toledo (US)
- Corresponding author
- Wang, Xiao-Fan
- Johansen, Terje
- Dou, Zhixun
- ORCID
- Wang, Yu
- Eapen, Vinay V.
- Liang, Yaosi
- Kournoutis, Athanasios
- Sherman, Marc Samuel
- Xu, Yanxin
- Li, Xianting
- Zhou, Xiaoting
- Corey, Kathleen E.
- Du, Kuo
- Ho, Chia-Kang
- Xie, Jing
- Ma, Xinyi
- Rieprecht, Ulrike
- Wang, Lu
- Liu, Jihe
- 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
- Venue
- Nature
- Published
- 2025-07-02
- Volume
- 644
- Issue
- 8077
- Pages
- 780-789
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC12888835
- OpenAlex
- W4411932295
- Cited by
- 30
- References
- 16
- Citations by year
- 2026: 21 · 2025: 7 · 2024: 1 · 2022: 1
- FWCI
- 19.41
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- Glenn Foundation for Medical Research
- Massachusetts General Hospital
- Harvard Catalyst (UL1TR002541)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Fondation pour la Recherche Médicale
- Norges Forskningsråd (249884)
- National Institutes of Health (UL1TR002541)
- Harvard Stem Cell Institute
- National Institute on Alcohol Abuse and Alcoholism (R01AA010154)
- National Institute on Aging (R21AG073894, R00AG053406, R01AG082785, R01AG072520, U54AG075936)
- National Cancer Institute (UH3CA268117, UG3CA268117, R01CA244564)
- National Institute of General Medical Sciences (R35GM137889)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK139370, K01DK135793, P30DK040561)
- National Institute of Neurological Disorders and Stroke (R01NS117590, R01NS060123)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- WSTF, ATG8, chronic inflammation, acute inflammation, chromatin remodeling, cell-penetrating peptides, nonalcoholic steatohepatitis, osteoarthritis, cellular senescence, lysosomal degradation
- MeSH terms
- Autophagosomes, Autophagy-Related Protein 8 Family, Acute Disease, Aging, Animals, Autophagy, Cell Nucleus, Chromatin, Chronic Disease, Disease Models, Animal, Female, Humans, Inflammation, Lysosomes, Male, Transcription Factors, Active Transport, Cell Nucleus, Chromatin Assembly and Disassembly, Mice
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