TY - JOUR
T1 - Mal (MyD88-adapter-like) is required for toll-like recepfor-4 signal transduction
AU - Fitzgerald, Katherine A.
AU - Palsson-Mcdermott, Eva M.
AU - Bowie, Andrew G.
AU - Jefferies, Caroline A.
AU - Mansell, Ashley S.
AU - Brady, Gareth
AU - Brint, Elizabeth
AU - Dunne, Aisling
AU - Gray, Pearl
AU - Harte, Mary T.
AU - McMurray, Diane
AU - Smith, Dirk E.
AU - Sims, John E.
AU - Bird, Timothy A.
AU - O'Neill, Luke A.J.
PY - 2001/9/6
Y1 - 2001/9/6
N2 - The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns1-9. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria5-7. All TLRs have a Toll/IL-1 receptor (TLR) domain, which is responsible for signal transduction1,2. MyD88 is one such protein that contains a TlR domain10,11. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling12-15; however, our understanding of how TLR-4 signals is incomplete15,16. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-κB, 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-κB by Mai requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TlR domain. A dominant negative form of Mal inhibits NF-κB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-κB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.
AB - The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns1-9. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria5-7. All TLRs have a Toll/IL-1 receptor (TLR) domain, which is responsible for signal transduction1,2. MyD88 is one such protein that contains a TlR domain10,11. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling12-15; however, our understanding of how TLR-4 signals is incomplete15,16. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-κB, 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-κB by Mai requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TlR domain. A dominant negative form of Mal inhibits NF-κB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-κB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.
UR - http://www.scopus.com/inward/record.url?scp=0035817925&partnerID=8YFLogxK
U2 - 10.1038/35092578
DO - 10.1038/35092578
M3 - Article
C2 - 11544529
AN - SCOPUS:0035817925
SN - 0028-0836
VL - 413
SP - 78
EP - 83
JO - Nature
JF - Nature
IS - 6851
ER -