Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction

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.

NF-κB and the immune response

“…TLR4 signaling is relatively unique amongst TLRs in that the effector adaptors are one step removed from the receptor. For example, MyD88 recruitment to the receptor complex depends upon the TIR-domain containing adapter protein (TIRAP, also known as Mal) (Fitzgerald et al, 2001;Horng et al, 2002;Yamamoto et al, 2002). TLR2 also requires TIRAP to bridge MyD88 to the receptor; however it is believed that other MyD88-utilizing TLRs directly recruit MyD88.…”

TLR signalling and activation of IRFs: revisiting old friends from the NF-κB pathway

“…A second TIR domain-containing adaptor protein was identified by two independent groups, and was named MyD88 adaptor-like (Mal), also known as TIR domaincontaining adaptor protein (TIRAP) [16,17]. However, the generation of Mal (TIRAP) knockout mice showed that this adaptor is not responsible for Myd88-independent signalling and instead acts as a bridging adaptor between Myd88 and TLR4 and TLR2 [18,19].…”

Genetic regulation of host responses to Salmonella infection in mice

“…71 ) and an MyD88-independent pathway involving the adapter protein TIRAP. 93,94 Activation of TLR4 by LPS leads to the induction of various host defense genes including pro-inflammatory cytokines such as IL1, IL6, IL8 and IL12, chemokines, costimulatory molecules (CD80 and CD86), MHC class II and NOS2 by APC cells. [95][96][97] Induction of CD80/CD86 and IL-12 by TLRs contributes to the initiation of adaptive immunity and the induction of TH1 effector responses.…”