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Oxidation-sensitive cysteines drive IL-38 amyloid formation

2024; Cell Press; Volume: 43; Issue: 11 Linguagem: Inglês

10.1016/j.celrep.2024.114940

2639-1856

Alejandro Díaz-Barreiro, Gea Cereghetti, Francisco G. Ortega, Jenna Tonacini, Dominique Talabot‐Ayer, Sylvie Kieffer‐Jaquinod, Vera M. Kissling, Arnaud Huard, Christopher Swale, Tuomas P. J. Knowles, Yohann Couté, Matthias Peter, Antonio Francés‐Monerris, Gaby Palmer,

Galectins and Cancer Biology

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.