Elucidating the role of ERK5 in the regulation of autophagy in regulatory T cells

Abstract

FoxP3+ regulatory T cells (Tregs) play crucial in maintaining immune system homeostasis. However, the molecular signaling mechanisms that drive Treg cell proliferation, differentiation, and function remain not fully understood. The Extracellular Signal-Regulated Kinase 5 (ERK5) is an atypical member of the mitogen-activated protein kinase (MAPK) family protein with canonical kinase function but can also regulate gene transcription independent of this canonical function. Although it is well described that TGF-² activates ERK5 in various cell types, the role of ERK5 in Treg cell differentiation and function remains unknown. Our results so far show that ERK5 is required not only for Treg cell differentiation but also for its lineage stability and suppressive activity. To explore the potential mechanism by which ERK5 regulates Treg cell biology, we performed RNA-seq analysis of ERK5-deficient Tregs. We found that ATG13, an essential component of the initiation of the autophagy machinery, was one of the most downregulated genes in those cells, suggesting a potential link between ERK5 and the autophagy pathway in Treg cells. PPAR-³, which is phosphorylated and activated by ERK5, is known to activate the transcription of autophagy-related genes, regulating the autophagy pathway. Interestingly, the impaired Treg cell differentiation found in ERK5-deficient T cells was restored when we activated PPAR-³ using a pharmacological tool. Therefore, our findings strongly suggest that ERK5 can promote Treg differentiation and function by regulating autophagy. Consequently, we intend to investigate further the molecular mechanisms involved in the ERK5-driven regulatory network in Treg cells. To reach this, we have set up a collaborative study with Prof. Anna Katharina Simon from Max Delbrüch Center in Germany, an expert researcher in the autophagy of immune cells. Therefore, we are applying for the BEPE fellowship program to spend 12 months in her laboratory to carry on this project. Understanding how ERK5 can regulate Treg cell differentiation and function may have important implications as a valuable target for treating autoimmune-mediated inflammatory diseases. (AU)