Abstract
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.
Highlights
2) is a member of the family of the TIR domain-containing adapter proteins involved in Toll-like receptor (TLR) signaling [3, 4]
Analysis of the amino acid sequence of Mal indicated a putative TRAF6-binding domain at amino acid position 188 – 193 consisting of Pro-Pro-Glu-Leu-Arg-Phe similar to that described for IRAK and TRIF (Table I)
Further analysis suggested that while Mal, TRIF, and TRAM all contain a putative TRAF6-binding motif, MyD88 does not, since the critical Glu residue that has been found to confer specificity for TRAF6 interaction is changed to Ile in the corresponding MyD88 sequence (Table I)
Summary
MyD88 adapter-like protein; TIR, Toll/IL-1 receptor; TLR, Toll-like receptor; TRIF, TIR-containing adapter inducing interferon ; TRAM, TRIF-related adapter molecule; LPS, lipopolysaccharide; IL, interleukin; HEK, human embryonic kidney; pI:C, poly(I)1⁄7poly(C); HA, hemagglutinin; JNK, c-Jun N-terminal kinase; MAP, mitogen-activated protein. 2) is a member of the family of the TIR domain-containing adapter proteins involved in Toll-like receptor (TLR) signaling [3, 4]. TRIF (TIR-containing adapter inducing interferon  or TICAM-1) (8 –10) is necessary for TLR3- and TLR4mediated activation of NF-B and another transcription factor IRF3, while TRAM (TRIF-related adapter molecule, termed TICAM-2) [11,12,13] is essential for TLR4 signals, including IRF3. TRIF was found to mediate TLR3-induced activation of NF-B via an association with TRAF6, independent of MyD88 and IRAK [15]. The motif is required for Mal to drive signals for NF-B activation and the interaction between Mal and TRAF6 for downstream signaling events This provides a distinguishing feature between Mal and MyD88 in TLR2- and TLR4-mediated responses
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