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Cell. 2014 Feb 13;156(4):705-16. doi: 10.1016/j.cell.2014.01.019.

A promiscuous lipid-binding protein diversifies the subcellular sites of toll-like receptor signal transduction.

Author information

1
Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
2
Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
3
Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA.
4
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
5
Immune Imaging Program, The Centenary Institute, Locked Bag 6, Newtown, NSW 2042, Australia; Discipline of Dermatology, University of Sydney, NSW 2006, Australia.
6
Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: jonathan.kagan@childrens.harvard.edu.

Abstract

The Toll-like receptors (TLRs) of the innate immune system are unusual in that individual family members are located on different organelles, yet most activate a common signaling pathway important for host defense. It remains unclear how this common signaling pathway can be activated from multiple subcellular locations. Here, we report that, in response to natural activators of innate immunity, the sorting adaptor TIRAP regulates TLR signaling from the plasma membrane and endosomes. TLR signaling from both locations triggers the TIRAP-dependent assembly of the myddosome, a protein complex that controls proinflammatory cytokine expression. The actions of TIRAP depend on the promiscuity of its phosphoinositide-binding domain. Different lipid targets of this domain direct TIRAP to different organelles, allowing it to survey multiple compartments for the presence of activated TLRs. These data establish how promiscuity, rather than specificity, can be a beneficial means of diversifying the subcellular sites of innate immune signal transduction.

PMID:
24529375
PMCID:
PMC3951743
DOI:
10.1016/j.cell.2014.01.019
[Indexed for MEDLINE]
Free PMC Article
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