Mal, more than a bridge to MyD88

Summary The family of type 1 transmembrane proteins known as Toll–like receptors (TLRs) provide early immune system recognition and response to infection. In order to transmit their signal to the nucleus and initiate activation of pro–inflammatory and anti–microbial genes, TLRs must initiate a cytoplasmic signalling cascade, which is alternately controlled by 6 known signalling adaptors. These signaling adaptors are crucial for activating the correct immune response to any given TLR / pathogen interaction. This review will focus on one of those adaptors, MyD88 adaptor–like (Mal), also known as TIRAP. Mal is critical for signalling by the best studied of the TLRs, the Gram negative bacterial lipopolysaccharide (LPS) sensor, TLR4. Mal's role in TLR2 signalling in response to activation of the bacterial lipopeptide receptor, TLR2, is more contentious. Mal is a component of the so–called ‘MyD88‐dependent pathway’ in TLR4 signalling. Recent advances in our understanding of the signalling pathways downstream of Mal highlight MyD88‐indpendent roles, thus positioning Mal as multifunctional and integral for the molecular control of bacterial infections as well as inflammatory diseases. Here we describe the sequence of molecular events involved in the signalling pathways controlled by Mal, and the importance of Mal in driving host protection against a variety of bacteria, with specific attention to the evidence for Mal's role in TLR2 signalling, recent structural findings that have altered our understanding of Mal signalling, and evidence that single nucleotide polymorphisms (SNPs) of Mal are responsible for variations in population level resistance and susceptibility to bacterial infection. © 2013 IUBMB Life, 65(9):777–786, 2013