A mammalian receptor for bacterial lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4), plays a beneficial role in controlling bacterial infections, but is also a main driver of aberrant inflammation in lethal sepsis. As a result, investigation of TLR4 signaling has been a major area of research. Despite this focus, our understanding of the mechanisms that regulate TLR4 activities remains primitive. Nowhere is our knowledge of TLR4 biology more lacking than at the receptor-proximal level, where many factors act in concert to regulate LPS signaling. Several recent studies have begun filling these gaps in our knowledge. In this review, we discuss the importance of these receptor proximal activities in the spatiotemporal regulation of TLR4 signaling, and suggest interesting areas for future research.

Deficiency of mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate (GGPP), a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, protein post-translational modification catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) cause autoinflammatory Familial Mediterranean Fever (FMF) syndrome. Here, we show that protein geranylgeranylation enables Toll-like receptor (TLR)-induced phosphatidylinositol-3-OH kinase PI(3)K) activation by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages deficient for GGTase I or p110δ exhibited constitutive interleukin-1β release that was MEFV-dependent, but NLRP3-, AIM2- and NLRC4- inflammasome independent. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows for an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.

The Gram-negative bacteria Yersinia pestis , causative agent of plague, is extremely virulent. One mechanism contributing to Y. pestis virulence is the presence of a type-three secretion system, which injects effector proteins, Yops, directly into immune cells of the infected host. One of these Yop proteins, YopJ, is proapoptotic and inhibits mammalian NF-κB and MAP-kinase signal transduction pathways. Although the molecular mechanism remained elusive for some time, recent work has shown that YopJ acts as a serine/threonine acetyl-transferase targeting MAP2 kinases. Using Drosophila as a model system, we find that YopJ inhibits one innate immune NF-κB signaling pathway (IMD) but not the other (Toll). In fact, we show YopJ mediated serine/threonine acetylation and inhibition of dTAK1, the critical MAP3 kinase in the IMD pathway. Acetylation of critical serine/threonine residues in the activation loop of Drosophila TAK1 blocks phosphorylation of the protein and subsequent kinase activation. In addition, studies in mammalian cells show similar modification and inhibition of hTAK1. These data present evidence that TAK1 is a target for YopJ-mediated inhibition.