Tenure-track Assistant Professor
Department of Biochemistry - UNIL
Our laboratory studies the signaling pathways and metabolic processes that allow immune cells to detect and respond to invading pathogens, and their implication in autoimmune diseases. A particular interest of the lab is the characterization of the role of solute carriers (SLCs) in immune functions and immunometabolism. These transporters play a critical role in cellular metabolism by mediating exchanges of nutrients, metabolites and chemical matter between the environment and the intracellular milieu as well as between subcellular organelles. Moreover, mounting evidence, including our studies on SLC38A9 (Rebsamen et al, Nature 2015) and SLC15A4 (Heinz et al, Nature 2020), suggests that SLCs can also work as signaling hubs controlling the activation of central transduction pathways. Our research aims at providing a better understanding of the signaling and metabolic processes controlling innate immune responses and autoimmune disease, and thereby contributing to identify potential targets for therapeutic intervention.
Characterization of SLC15A4 and the innate immune adaptor TASL in (auto)immunity
The initiation of immune responses relies on the recognition of invading pathogens by a variety of pattern recognition receptors (PRR) located in different cellular compartments. Endosomal Toll-like receptors (TLRs) play a crucial role in innate immune activation by detecting microbial-derived nucleic acids. Importantly, dysregulation of these processes leading to aberrant activation by endogenous ligands is associated with autoinflammatory and autoimmune conditions, including systemic lupus erythematosus (SLE).
By studying SLC15A4, an endolysosomal SLC implicated in endosomal TLR function and SLE by both human genetics and animal studies, we recently identified the interacting protein TASL as a novel innate immune adaptor (Heinz et al, Nature 2020). Upon TLR stimulation, TASL mediates the recruitment and activation of the transcription factor IRF5. Deletion of SLC15A4 or TASL impairs therefore endolysosomal TLR responses. Mechanistically TASL recruits IRF5 via a specific pLXIS motif, which in the three canonical innate immune adaptors MAVS, STING and TRIF, mediates binding and activation of IRF3.
The current focus of the lab is the characterization of the molecular mechanisms and the regulatory processes controlling the SLC15A4/TASL/IRF5 pathway as well as the definition of its pathophysiological relevance in innate immune responses and autoimmunity. To achieve these goals, we employ state-of-the-art biochemical, molecular and cell biological approaches (including proteomics and CRISPR/Cas9-based screening technologies) as well as in vivo studies.
- Innate Immunity
- Solute Carriers