Special Seminar by Manuele Rebsamen from the University of Lausanne on the molecular players of autoimmunity

Manuele Rebsamen Biography: He received his PhD in 2011 from the University of Lausanne working in the laboratory of Jürg Tschopp on innate immunity and cell death pathways, with a main focus on the characterization of pathogen recognition receptors involved in viral sensing. Manuele then joined the laboratory of Prof. Giulio Superti-Furga at CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences as an EMBO and Marie Sklodowaska-Curie postdoctoral fellow. In Vienna, he investigated the role of solute carrier (SLC) proteins first in nutrient sensing and cell growth, and subsequently in cell death and innate immunity, which led to the identification of the novel innate immune adaptor protein TASL. In August 2020, he joined the Department of Immunobiology (formerly Biochemistry) as a Tenure-track Assistant Professor. His research will focus on the role of SLCs and TASL in innate immune responses, autoimmunity, and immunometabolism.

Abstract for the seminar: Nucleic acid sensing by endolysosomal Toll-like receptors (TLRs) plays a crucial role in innate immune responses to invading pathogens. In contrast, aberrant activation of these pathways is associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). The endolysosomal solute carrier family 15 member 4 (SLC15A4) is required for TLR7, TLR8 and TLR9-induced inflammatory responses and for disease development in different SLE murine models, highlighting its potential as drug target. SLC15A4 has been proposed to affect TLR7-9 activation through its transport activity, but its mechanistic role remained largely unclear.

During this talk, I will summarize our work investigating the function of SLC15A4 that led to the the discovery of a novel innate immune adaptor, TASL, which controls TLR7/9-induced responses by assembling in an IRF5-activating signalling complex with SLC15A4 (Heinz et al, Nature 2020). Notably, all the components of this signaling axis are associated to SLE in GWAS. I will further present recent work highlighting the crucial role for IRF5 activation of SLC15A4-mediated recruitment of TASL to the endolysosomal compartment and demonstrating that this complex is “druggable” (Zhang et al, Cell Reports, 2023; Boeszoermenyi et al, Nat. Commun. 2023). Finally, I will discuss unpublished data showing the involvement of the SLC15A4-TASL complex in antiviral and autoimmune responses in vivo. Althogether, these findings strongly support targeting the SLC15A4-TASL complex as a potential therapeutic strategy for SLE and related diseases.

 

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