June 2021 - Leonhard Heinz

Dr. Leonhard Heinz

MedUni Wien RESEARCHER OF THE MONTH June 2021

TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9

Toll-like receptors (TLRs) are important sensor proteins of the immune system that detect pathogen-associated molecular patterns, such as bacterial cell wall components or viral nucleic acids. Receptor signaling relies on specific downstream adaptor proteins that are required to regulate the immune response. In this study, we have identified a novel adaptor protein, TASL, that is genetically associated with systemic lupus erythematosus and that connects endosomal TLRs with the pro-inflammatory transcription factor IRF5. Mechanistically, TASL harbors an activation motif necessary for IRF5 recruitment to the receptor complex and subsequent transcriptional activation. This discovery provides a molecular explanation for the involvement of TASL in autoimmunity and highlights this pathway as a new potential target for pharmacologic intervention.

Selected Literature

1. Heinz, L.X., et al., TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7–9. Nature, 2020. 581(7808): p. 316-322.
2. Kawai, T. and S. Akira, The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol, 2010. 11(5): p. 373-84.
3. Pelka, K., et al., Nucleic acid-sensing TLRs and autoimmunity: novel insights from structural and cell biology. Immunol Rev, 2016. 269(1): p. 60-75.
4. Blasius, A.L., et al., Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells. Proc Natl Acad Sci U S A, 2010. 107(46): p. 19973-8.
5. Han, J.W., et al., Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet, 2009. 41(11): p. 1234-7.
6. Baccala, R., et al., Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus. Proc Natl Acad Sci U S A, 2013. 110(8): p. 2940-5.
7. Kobayashi, T., et al., The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity, 2014. 41(3): p. 375-388.