Etude des mécanismes moléculaires impliqués dans la localisation en surface de cytokines de la famille de l’IL-12
Responsable de l’encadrement : Dr Odile Devergne
Centre de recherche sur l’Inflammation,
Résumé du Projet de Stage
Interleukin (IL)-12 family cytokines are proteins involved in cell-to-cell-communication and major regulators of innate and adaptive immune responses. They play pivotal roles in regulating inflammation through various mechanisms including the regulation of immune checkpoints, and have emerged as promising targets or tools for immunotherapeutic interventions in different inflammatory disorders and in cancers. The four main members of this family, IL-12, IL-23, IL-27 and IL-35, are characterized by an atypical structure – all are heterodimers – and a complex process of biogenesis. Another layer of complexity is their trafficking, as recent data from the literature and the team have indicated that several IL-12 family members may use non-conventional trafficking routes to reach their final destinations. Thus, while cytokines are expected to be produced as secreted soluble proteins, some IL-12 family members can be detected at the cell surface or in extracellular vesicles. This atypical localization might impact their biological activity and/or their accessibility to neutralizing antibodies developed for clinical use. The molecular mechanisms underlying the ultimate localization of IL-12 family cytokines remain largely underexplored. Gaining insights into these mechanisms will have a major impact on our understanding of how IL-12 family signaling is regulated and how it can be efficiently targeted for therapeutic purposes.
In the team, we have developed a longtime expertise for two IL-12 cytokines sharing the common subunit EBI3: IL-27 (EBI3/p28 heterodimer) and IL-35 (EBI3/p35). Recently, by using a biochemical approach, we have identified several EBI3 interactants that might regulate its trafficking. The goal of the master project is to investigate the potential role of these interactants in the trafficking of EBI3 and its partners and in the formation of the cell surface-bound and vesicular forms of IL-27 and IL-35.
This specific aim will be addressed in in vitro experiments by combining gene silencing experiments with biochemical analyses, microscopy, and flow cytometry.
Dernières Publications en lien avec le projet :
- Hildenbrand K, Aschenbrenner I, Franke FC, DEVERGNE O*, Feige MJ*. Biogenesis and engineering of interleukin 12 family cytokines. Trends Biochem Sci 2022 Nov, 47:936-949. PMID: 35691784; * corresponding authors
- Cavé MC, Maillard S, Hildenbrand K, Mamelonet C, Feige MJ, DEVERGNE O. Glycosaminoglycans bind human IL-27 and regulate its activity. Eur J Immunol 2020 Oct, 50:1484-1499. PMID:32483835.
- Larousserie F, Kebe D, Huynh T, Audebourg A, Tamburini J, Terris B, DEVERGNE O. Evidence for IL-35 expression in diffuse large B-cell lymphoma and impact on the patient’s prognosis. Front Oncol 2019 Jun, 9:563. PMID:31316915.
- Müller SI, Friedl A, Aschenbrenner I, Esser-von Bieren J, Zacharias M, DEVERGNE O*, Feige MJ*. A folding switch regulates interleukin 27 biogenesis and secretion of its alpha subunit as a cytokine. Proc Natl Acad Sci USA 2019 Jan, 116:1585-1590. PMID:30651310. * corresponding authors
- Larousserie F, Bsiri L, Dumaine V, Dietrich C, Audebourg A, Radenen-Bussière B, Anract P, Vacher-Lavenu MC,DEVERGNE O. Frontline Science : Human bone cells as a source of IL-27 under inflammatory conditions: role of TLRs and cytokines. J Leukoc Biol. 2017 Jun;101(6):1289-1300. PMID: 27677834
Ce projet s’inscrit dans la perspective d’une thèse
Ecole Doctorale de rattachement : ED394
Equipe d’Accueil :
Intitulé de l’Unité : Centre de recherche sur l’Inflammation, INSERM U1149
Nom du Responsable de l’Unité : Rénato Monteiro
Nom du Responsable de l’Équipe : Loredana Saveanu
Adresse : Faculté de Médecine Bichat, 16 rue H. Huchard, 75018 Paris