Differential expression of membrane-bound and cytosolic PRRs in response to infection. Time-dependent log2 fold changes of mRNAs from non-interacting and interacting cells are depicted for the listed gene products, and interactions between the encoded proteins are indicated by arrows. (a) Differentially expressed mRNAs encoding proteins involved in early (MyD88-dependent) and late (TRIF-dependent) NF-κB signaling. Binding of bacterial LPS to TLR4 activates two distinct signaling cascades that lead to expression of inflammatory cytokines via activation of the Rel/NF-κB transcription factor family. Activation of MyD88 results in signal transmission via interleukin-1 receptor-associated kinases (IRAKs) that in turn activate TRAF6. This part of the signaling pathway, however, is not functional in HeLa cells (gray boxes) because of lacking MD2 expression. TRAF6 signaling results in activation of the kinase TAK1 complex that phosphorylates NEMO (IKK-γ), which in turn leads to phosphorylation of the inhibitor subunits of NF-κB (IκBs) via canonical IKK-β. Phosphorylated IκBs are degraded by the ubiquitin-dependent pathway, thereby releasing NF-κB, which subsequently translocates to the nucleus to function as a transcription factor (dashed arrow). TRIF-dependent signaling is also stimulated via activation of TLR3 by binding of double stranded RNA, and enhances activation of the kinase TAK1 complex by formation of a multimeric protein signaling complex comprising TRAF6, TRADD, Pellino-1 (PELI1) and RIP1 (RIPK1). (b) Differential expression of other cytosolic PRRs that modulate the NF-κB response by cross-signaling. Nod-like receptors comprise four subfamilies, and expression profiles of the mRNAs encoding NAIP (NLRB family), NOD1, and NLRC5 (NLRC family) as well as NLRP8 and NLRP11 (NLRP family) are shown along with those from the RIG-I-like receptors LGP2 (DHX58), RIG-I (DDX58), and MDA5 (IFIH1).