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Innate immunity

TLR9 mutations reveal a new level of self tolerance

Nature Reviews Immunology volume 12, page 7 (2012)Cite this article

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expression by haematopoietic stem cells (HSCs) of a TLR9 mutant that does not depend on proteolysis for its activation results in autoinflammation

Cleavage of the TLR9 ectodomain in the endolysosome is thought to allow a membrane-proximal conformational change in response to ligand binding that facilitates the recruitment of the adaptor molecule MYD88 and initiates TLR9 signalling. So, the authors reasoned that substitution of the atypical transmembrane domain of TLR9 by the more hydrophobic transmembrane domain of TLR3 may spare the need for this conformational change. Indeed, expression of such a TLR9 mutant (TLR9TM-MUT) in TLR9-deficient myeloid cells resulted in MYD88 recruitment to TLR9 in response to stimulation with CpG oligodeoxynucleotides, even after inhibition of proteolytic processing. This processing-independent activation of TLR9 was also triggered by plate-bound CpG oligodeoxynucleotides, indicating that TLR9TM-MUT, unlike wild-type TLR9, can be activated both in the endolysosomal compartment and on the cell surface. Interestingly, cell-surface expression of TLR9TM-MUT was higher than that of wild-type TLR9.

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ORIGINAL RESEARCH PAPER

  1. Mouchess, M. L. et al. Transmembrane mutations in Toll-like receptor 9 bypass the requirement for ectodomain proteolysis and induce fatal inflammation. Immunity 35, 721–732 (2011)Article

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  1. Maria Papatriantafyllou
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Papatriantafyllou, M. TLR9 mutations reveal a new level of self tolerance. Nat Rev Immunol 12, 7 (2012). https://doi.org/10.1038/nri3134

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