Abstract
The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction. MyD88 is one such protein that contains a TIR domain. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling; however, our understanding of how TLR-4 signals is incomplete. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome. Mal activates NF-kappaB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. Mal can form homodimers and can also form heterodimers with MyD88. Activation of NF-kappaB by Mal requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TIR domain. A dominant negative form of Mal inhibits NF-kappaB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-kappaB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.
Original language | English |
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Pages (from-to) | 78-83 |
Number of pages | 6 |
Journal | Nature |
Volume | 413 |
Issue number | 6851 |
DOIs | |
Publication status | Published - 06 Sept 2001 |
Keywords
- Adaptor Proteins, Signal Transducing
- Amino Acid Sequence
- Animals
- Antigens, Differentiation
- Carrier Proteins
- Cell Line
- Drosophila Proteins
- Humans
- Interleukin-1 Receptor-Associated Kinases
- Lipopolysaccharides
- Membrane Glycoproteins
- Mice
- Molecular Sequence Data
- Myeloid Differentiation Factor 88
- NF-kappa B
- Protein Kinases
- RNA, Messenger
- Receptors, Cell Surface
- Receptors, Immunologic
- Receptors, Interleukin-1
- Sequence Homology, Amino Acid
- Signal Transduction
- Toll-Like Receptor 2
- Toll-Like Receptor 4
- Toll-Like Receptor 9
- Toll-Like Receptors
- Transfection
- Xenopus
- Xenopus Proteins