Schematic diagram of RHIM-dependent signaling. Common steps in RHIM-dependent interactions are shown for TLR3/TLR4 signaling via TRIF (left), as summarized in (19), as well as for DAI (right), described in this report. When triggered, DAI and TRIF recruit RIP1 in a pathway that activates NF-κB by release of RelA from the IKK complex. TRIF and DAI also induce TBK1-mediated activation of IRF3. Together, RelA (NF-κB) and IRF3 promote Type I IFN gene expression. RIP3 regulates RIP1-dependent NF-κB activation in opposite ways, depressing RHIM-dependent TRIF-mediated events, but stimulating RHIM-dependent DAI-mediated events. Red circles indicate the RHIM of DAI, TRIF, RIP1, and RIP3. White circles on DAI indicate RLR-B and -C.