Psoriasis-associated variant Act1 D10N with impaired regulation by Hsp90

Act1 is an essential adaptor molecule in IL-17-mediated signaling and is recruited to the IL-17 receptor upon IL-17 stimulation. Here, we report that Act1 is a client protein of the molecular chaperone, Hsp90. The Act1 variant (D10N) linked to psoriasis susceptibility is defective in its interaction with Hsp90, resulting in a global loss of Act1 function. Act1-/- mice modeled the mechanistic link between Act1 loss of function and psoriasis susceptibility. Although Act1 is necessary for IL-17-mediated inflammation, Act1-/- mice exhibited a hyper TH17 response and developed spontaneous IL-22-dependent skin inflammation. In the absence of IL-17-signaling, IL-22 is the main contributor to skin inflammation, providing a molecular mechanism for the association of Act1 (D10N) with psoriasis susceptibility

Protection from RNA and DNA viruses by IL-32.

Item does not contain fulltextSeveral studies have documented a proinflammatory role for IL-32, which induces IL-1alpha, IL-1beta, IL-6, TNF, and chemokines via NF-kappaB, p38MAPK, and AP-1. However, IL-32 also participates in the responses to infection with viruses such as HIV-1 and influenza. In this study, we explored these antiviral properties of IL-32. Vital staining assays demonstrated that low concentrations (5-10 ng/ml) of rIL-32gamma protected epithelial WISH cells from vesicular stomatitis virus-induced cell death. By lactate dehydrogenase assays, treatment with IL-32gamma resulted in a 3- to 4-fold decrease in viral load. Specific silencing of IL-32 revealed that the antiviral responses triggered by the synthetic analogs of ssRNA viruses (polyuridine) and dsRNA viruses (polyinosinic-polycytidylic acid) were significantly weaker (2- to 3-fold more virus) in WISH cells in the absence of IL-32. Importantly, we discovered that the polyinosinic-polycytidylic acid-induced increase in production of IFN-alpha in human PBMC was nearly completely abolished when IL-32 was silenced. Moreover, we observed that IL-32 antagonizes the DNA virus HSV-2 in epithelial Vero cells as well as in human umbilical cord endothelial cells, as production of HSV-2 increased 8-fold upon silencing of IL-32 (p < 0.001). Mechanistically, we found that IL-32 used the PKR-eIF-2alpha as well as the MxA antiviral pathways. Unexpectedly, a considerable part of the antiviral properties of IL-32 was not dependent on IFNs; specific blockade of IFN activity reduced the antiviral properties of IL-32 only moderately. In conclusion, these data suggest a central role for IL-32 in the immune response to RNA and DNA viruses, which may be exploitable for clinical use in the future

Emergence of a Wave of Wnt Signaling that Regulates Lung Alveologenesis by Controlling Epithelial Self-Renewal and Differentiation

Alveologenesis is the culmination of lung development and involves the correct temporal and spatial signals to generate the delicate gas exchange interface required for respiration. Using a Wnt-signaling reporter system, we demonstrate the emergence of a Wnt-responsive alveolar epithelial cell sublineage, which arises during alveologenesis, called the axin2+ alveolar type 2 cell, or AT2Axin2. The number of AT2Axin2 cells increases substantially during late lung development, correlating with a wave of Wnt signaling during alveologenesis. Transcriptome analysis, in&nbsp;vivo clonal analysis, and ex&nbsp;vivo lung organoid assays reveal that AT2sAxin2 promote enhanced AT2 cell growth during generation of the alveolus. Activating Wnt signaling results in the expansion of AT2s, whereas inhibition of Wnt signaling inhibits AT2 cell development and shunts alveolar epithelial development toward the alveolar type 1 cell lineage. These findings reveal a wave of Wnt-dependent AT2 expansion required for lung alveologenesis and maturation

Emergence of a Wave of Wnt Signaling that Regulates Lung Alveologenesis by Controlling Epithelial Self-Renewal and Differentiation

Alveologenesis is the culmination of lung development and involves the correct temporal and spatial signals to generate the delicate gas exchange interface required for respiration. Using a Wnt-signaling reporter system, we demonstrate the emergence of a Wnt-responsive alveolar epithelial cell sublineage, which arises during alveologenesis, called the axin2+ alveolar type 2 cell, or AT2Axin2. The number of AT2Axin2 cells increases substantially during late lung development, correlating with a wave of Wnt signaling during alveologenesis. Transcriptome analysis, in&nbsp;vivo clonal analysis, and ex&nbsp;vivo lung organoid assays reveal that AT2sAxin2 promote enhanced AT2 cell growth during generation of the alveolus. Activating Wnt signaling results in the expansion of AT2s, whereas inhibition of Wnt signaling inhibits AT2 cell development and shunts alveolar epithelial development toward the alveolar type 1 cell lineage. These findings reveal a wave of Wnt-dependent AT2 expansion required for lung alveologenesis and maturation

A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis.

Although IL-17 is emerging as an important cytokine in cancer promotion and progression, the underlining molecular mechanism remains unclear. Previous studies suggest that IL-17 (IL-17A) sustains a chronic inflammatory microenvironment that favors tumor formation. Here we report a novel IL-17–mediated cascade via the IL-17R–Act1–TRAF4–MEKK3–ERK5 positive circuit that directly stimulates keratinocyte proliferation and tumor formation. Although this axis dictates the expression of target genes Steap4 (a metalloreductase for cell metabolism and proliferation) and p63 (a transcription factor for epidermal stem cell proliferation), Steap4 is required for the IL-17–induced sustained expansion of p63(+) basal cells in the epidermis. P63 (a positive transcription factor for the Traf4 promoter) induces TRAF4 expression in keratinocytes. Thus, IL-17–induced Steap4-p63 expression forms a positive feedback loop through p63-mediated TRAF4 expression, driving IL-17–dependent sustained activation of the TRAF4–ERK5 axis for keratinocyte proliferation and tumor formation