Manuele Rebsamen 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 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.
The Rebsamen 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 and SLC15A4, 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. 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.
Key words: Innate Immunity, Solute Carriers, Signaling, Pattern Recognition Receptors, Autoimmunity
Heinz LX, Lee J, Kapoor U, Kartnig F, Sedlyarov V, Papakostas K, César-Razquin A, Essletzbichler P, Goldmann U, Stefanovic A, Bigenzahn JB, Scorzoni S, Pizzagalli MP, Bensimon A, Müller AC, King FJ, Li J, Girardi E, Mbow ML, Whitehurst CE, Rebsamen M#, Superti-Furga G# (#Corresponding authors). TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. Nature, 2020 May;581(7808):316-322. doi: 10.1038/s41586-020-2282-0
Fauster A*, Rebsamen M*,#, Willmann KL, César-Razquin A, Girardi E, Bigenzahn JW, Schischlik F, Scorzoni S, Bruckner M, Konecka J, Hörmann K, Heinz LX, Boztug K and Superti-Furga G# (*Equal contribution, #Corresponding authors). Systematic genetic mapping of necroptosis identifies SLC39A7 as a modulator of death receptor trafficking. Cell Death and Differentiation, 2019 Jun;26(6):1138-1155. doi: 10.1038/s41418-018-0192-6
Rebsamen M, Pochini L, Stasyk T, de Araújo ME, Galluccio M, Kandasamy RK, Snijder B, Fauster A, Rudashevskaya EL, Bruckner M, Scorzoni S, Filipek PA, Huber KV, Bigenzahn JW, Heinz LX, Kraft C, Bennett KL, Indiveri C, Huber LA, Superti-Furga G. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature, 2015 Mar 26, 519(7544):477-8. doi: 10.1038/nature14107
Manuele Rebsamen Publications
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