Summary IL-1β produced by phagocytes is important for protection against Staphylococcus aureus. Secretion of this cytokine requires both activation of a transcriptional signal to stimulate production of pro-IL-1β, and a second signal to stimulate processing by inflammasome complexes and release of the mature cytokine. We show here that phagocytosis and lysozyme-based degradation of bacterial cell walls are functionally coupled to activation of NLRP3 inflammasomes and secretion of IL-1β in response to live S. aureus and to S. aureus peptidoglycan. Further a S. aureus enzyme, peptidoglycan O-acetyl transferase A, previously demonstrated to make cell wall peptidoglycan resistant to lysozyme strongly suppresses inflammasome activation and inflammation in vitro and in vivo. This is the first demonstration of a case whereby a bacterium specifically subverts IL-1β secretion through chemical modification of its cell wall peptidoglycan.

The COP9/signalosome complex is conserved from plant to mammalian cells. In Arabidopsis, it regulates the nuclear abundance of COP1, a transcriptional repressor of photomorphogenic development [1] [2]. All COP (constitutive photomorphogenesis) mutants inappropriately express genes that are normally repressed in the dark. Eight subunits (Sgn1-Sgn8) of the homologous mammalian complex have been purified [3] [4]. Several of these have been previously identified through genetic or protein interaction screens. No coherent model for COP9/signalosome function has yet emerged, but a relationship with cell-cycle progression by transcriptional regulation, protein localisation or protein stability is possible. Interestingly, the COP9/signalosome subunits possess domain homology to subunits of the proteasome regulatory lid complex [5] [6]. Database searches indicate that only Sgn5/JAB1 is present in Saccharomyces cerevisiae, precluding genetic analysis of the complex in cell-cycle regulation. Here we identify a subunit of the signalosome in the fission yeast Schizosaccharomyces pombe through an analysis of the DNA-integrity checkpoint. We provide evidence for the conservation of the COP9/signalosome complex in fission yeast and demonstrate that it functions during S-phase progression.

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Since Toll-like receptor (TLR) signaling was found crucial for the activation of innate and adaptive immunity, it has been the focus of immunological research. There are at least 13 identified mammalian TLRs, to date, that share similarities in their extracellular and intracellular domains. A vast number of ligands have been identified that are specifically recognized by different TLRs. As a response the TLRs dimerize and their signaling is initiated. The molecular basis of that signaling depends on the conserved part of their intracellular domain; namely the Toll/IL-1 receptor (TIR) domain. Upon TLR dimerization a TIR-TIR structure is formed that can recruit TIR-containing intracellular proteins that mediate their signaling. For this reason these proteins are named adapters. There are five adapters identified so far named myeloid differentiation primary response protein 88 (MyD88), MyD88-adapter like (Mal) or TIR domain-containing adapter (TIRAP), TIR domain-containing adapter inducing interferon-beta (IFN-beta) (TRIF) or TIR-containing adapter molecule-1 (TICAM-1), TRIF-related adapter molecule (TRAM) or TICAM-2, and sterile alpha and HEAT-Armadillo motifs (SARM). The first four play a fundamental role in TLR-signaling, defining which pathways will be activated, depending on which of these adapters will be recruited by each TLR. Among these adapter proteins MyD88 and TRIF are now considered as the signaling ones and hence the TLR pathways can be categorized as MyD88-dependent and TRIF-dependent.

Host anti-CdtB antibodies cross-react with vinculin in ICC and myenteric ganglia, required for normal gut motility. Circulating antibody levels and loss of vinculin expression correlate with number of C. jejuni exposures and SIBO, suggesting that effects on vinculin are important in the effects of C. jejuni infection on the host gut.