ABSTRACT
In subjects with peculiar susceptibility to severe infections by common pyogenic bacteria, mutations of interleukin-1 receptor-associated kinase proteins (IRAK)1 and IRAK4 had been identified. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. In two patients with sequential or repeated invasive infections: herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and Streptococcus pneumoniae bacteremia with candidemia respectively, novel mutations of IRAK2 were identified. These mutations compromised the capacity to ubiquinate (or functionally modify) the signal adaptor tumor necrosis factor receptor-associated factor 6. The result is impairment of the cytokine tumor necrosis factor-alpha production. This susceptibility to a varied range of pathogens underlines a potential central role played by IRAK2 in mediating host defense in infectious diseases.
ABSTRACT
ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other MDA5 signaling proteins does not yield the same rescue. Here, we show that ablation of MDA5 in a liver-specific Adar knockout (KO) murine model fails to rescue hepatic abnormalities caused by ADAR1 loss. Ifih1;Adar double KO (dKO) hepatocytes accumulate endogenous dsRNAs, leading to aberrant transition to a highly inflammatory state and recruitment of macrophages into dKO livers. Mechanistically, progranulin (PGRN) appears to mediate ADAR1 deficiency-induced liver pathology, promoting interferon signaling and attracting epidermal growth factor receptor (EGFR)+ macrophages into dKO liver, exacerbating hepatic inflammation. Notably, the PGRN-EGFR crosstalk communication and consequent immune responses are significantly repressed in ADAR1high tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion.
Subject(s)
Adenosine Deaminase , ErbB Receptors , Hepatocytes , Interferon-Induced Helicase, IFIH1 , Liver , Macrophages , Mice, Knockout , Progranulins , Animals , Adenosine Deaminase/metabolism , Adenosine Deaminase/genetics , ErbB Receptors/metabolism , Macrophages/metabolism , Macrophages/immunology , Progranulins/metabolism , Progranulins/genetics , Liver/metabolism , Liver/immunology , Liver/pathology , Hepatocytes/metabolism , Mice , Interferon-Induced Helicase, IFIH1/metabolism , Interferon-Induced Helicase, IFIH1/genetics , Signal Transduction , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Intercellular Signaling Peptides and Proteins/genetics , Mice, Inbred C57BL , RNA, Double-Stranded/metabolism , RNA EditingABSTRACT
Innate immune adaptor proteins are critical components of the innate immune system that propagate pro-inflammatory responses from their upstream receptors, and lead to pathogen clearance from the host. Bacterial pathogens have developed strategies to survive inside host cells without triggering the innate immune surveillance in ways that are still not fully understood. Here, it is reported that Pseudomonas aeruginosa induces its quorum sensing mechanism after macrophage engulfment. Further investigation of its secretome identified a quorum sensing regulated product, LasB, is responsible for innate immune suppression depending on the MyD88-mediated signaling. Moreover, it is showed that this specific type of pathogen-mediated innate immune suppression is due to the enzymatic digestion of the death domains of the innate immune adaptors, mainly MyD88, and attributed to LasB's large substrate binding groove. Lastly, it is demonstrated that the secretion of LasB from P. aeruginosa directly contributed to MyD88 degradation within macrophages. Hence, it is discovered an example of bacterial quorum sensing-regulated cellular innate immune suppression by direct cleavage of immune adaptors.
Subject(s)
Peptide Hydrolases , Quorum Sensing , Peptide Hydrolases/metabolism , Death Domain , Myeloid Differentiation Factor 88/metabolism , Endopeptidases/metabolism , Immunity, InnateABSTRACT
Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, their mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIINDUPA. Biochemically, self-assembled NLRP1-CARD filaments are sufficient to drive ASC speck formation in cultured human cells-a process that is greatly enhanced by NLRP1-FIINDUPA which forms oligomers in vitro. The cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments, solved here at 3.7 Å, uncover unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide structural insight into the mechanisms of activation for human NLRP1 and CARD8 and reveal how highly specific signaling can be achieved by heterotypic CARD interactions within the inflammasome complexes.