Mal interacts with tumor necrosis factor receptor-associated factor (TRAF)-6 to mediate NF-kappaB activation by toll-like receptor (TLR)-2 and TLR4.
The Toll-interleukin-1 receptor domain-containing adapter Mal (MyD88 adapter-like protein) is involved in Toll-like receptor (TLR)-2 and TLR4 signal transduction. However, no studies have yet identified a function for Mal distinct from the related adapter MyD88. In this study, we have identified a putative TRAF6 interaction site in Mal but not in MyD88 and we demonstrate that Mal can be co-immunoprecipitated with TRAF6. Overexpression of MalE190A, which contains a mutation within the TRAF6-binding motif, failed to induce the expression of an NF-kappaB-dependent reporter gene, p65-mediated transactivation of gene expression, or activation of Jun N-terminal kinase or p42/p44 MAP kinase, which are induced with wild type Mal. MalE190A inhibited TLR2- and TLR4-mediated activation of NF-kappaB. These results identify a specific role for Mal in TLR-mediated signaling in regulating NF-kappaB-dependent gene transcription via its interaction with TRAF6.
Mansell
Ashley
A
Centre for Functional Genomics and Human Disease, Monash Institute of Reproduction and Development, Monash University, Melbourne, Victoria 3168, Australia. ashley.mansell@med.monash.edu.au
Brint
Elizabeth
E
Gould
Jodee A
JA
O'Neill
Luke A
LA
Hertzog
Paul J
PJ
D002460:Cell Line; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors