Signal pathway activation by the main TLR and CLR receptors that detect Candida. Signalling through TLRs proceeds mainly via TRAF6 with a variety of adaptor proteins acting as intermediaries between receptor and TRAF6. Foremost among these is MyD88 which is utilised by all known TLRs except TLR3. As well as MyD88, there are other adaptor molecules, including TRIF, MAL, and TRAM, with the different TLRs using different combinations of these adaptors. Activation of these adaptors leads to activation of IRAK1, 2, and 4 followed by ubiquitination of TRAF6 which leads to subsequent activation of downstream signalling pathways. Signalling through CLRs utilises cytoplasmic ITAM domains to interact with the SYK adaptor molecule, activating the Card-9-Bcl10-Malt1 protein complex. Some CLRs, such as Dectin-1, include a modified ITAM domain in their cytoplasmic domain. Others, such as Dectin-2, associate with other receptor molecules, notably the FcRγ and DAP12 proteins, which possess the ITAM domain that transduces the signal into the cell. In all cases, the net effect is to activate the MAPK and NF-κB pathways, leading to upregulation of specific gene transcription. In addition to this, TLRs are also known to activate transcription via members of the IRF family, including IRF3, IRF5, and IRF7.
