1. Oxidation-sensitive cysteines drive IL-38 amyloid formation.
- Author
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Diaz-Barreiro A, Cereghetti G, Ortega Sánchez FG, Tonacini J, Talabot-Ayer D, Kieffer-Jaquinod S, Kissling VM, Huard A, Swale C, Knowles TPJ, Couté Y, Peter M, Francés-Monerris A, and Palmer G
- Subjects
- Humans, Keratinocytes metabolism, Oxidative Stress, Interleukins metabolism, Interleukins chemistry, Protein Aggregates, Oxidation-Reduction, Amyloid metabolism, Cysteine metabolism
- Abstract
Interleukin (IL)-1 family cytokines are essential for host defense at epithelial barriers. The IL-1 family member IL-33 was recently linked to stress granules (SGs). Formation of SGs and other biomolecular condensates is promoted by proteins containing low-complexity regions (LCRs). Computational analysis predicts LCRs in six of the 11 IL-1 family members. Among these, IL-38 contains a long LCR including two amyloid cores. IL-38 localizes to intracellular granules in keratinocytes under oxidative stress (OS) and forms OS-induced amyloid aggregates in cells and in vitro. Interestingly, soluble and aggregated IL-38 are released from keratinocytes in an exosome-enriched extracellular vesicle fraction. Disulfide-bond mapping, in silico modeling, and mutational analysis suggest that oxidation-sensitive cysteines act as redox switches to alter IL-38 conformation and promote its aggregation. Finally, the presence of IL-38 granules in human epidermis facing environmental OS suggests that oxidation-induced amyloidogenesis, as an intrinsic property of IL-38, supports barrier function., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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