Project description:The importance of unanchored Ub in innate immunity has been shown only for a limited number of unanchored Ub-interactors. We investigated what additional cellular factors interact with unanchored Ub and whether unanchored Ub plays a broader role in innate immunity. To identify unanchored Ub-interacting factors from murine lungs, we used His-tagged recombinant poly-Ub chains as bait. These chains were mixed with lung tissue lysates and protein complexes were isolated with Ni-NTA beads. Sample elutions were subjected to mass spectrometry (LC-MSMS) analysis.
Project description:<p>Healthy behavioral patterns could modulate organ functions to enhance the body’s immunity. However, whether exercise regulates antiviral innate immunity remains elusive. Here, we found that exercise promotes type-I IFN (IFN-I) production in the liver and enhances IFN-I immune activity of the body. Despite the possibility that many exercise-induced factors could regulate IFN-I production, we identified Gpld1 as a crucial molecule and the liver as the major organ to promote IFN-I production after exercise. Exercise largely loses the efficiency to induce IFN-I in Gpld1-/- mice. Further studies demonstrated that exercise-produced 3-hydroxybutanoic acid (3-HB) critically induces Gpld1 expression in the liver. Gpld1 blocks the PP2A-IRF3 interaction and therefore enhances IRF3 activation and IFN-I production, and improves the body’s antiviral ability. This study reveals that the exercise behavior improves antiviral innate immunity by linking the liver metabolism to systemic IFN-I activity, and uncovers an unknown function of liver cells in innate immunity.</p>
Project description:Across metazoans, innate immunity is vital in defending organisms against viral infection. In mammals, antiviral innate immunity is orchestrated by interferon signaling, activating the STAT transcription factors downstream of the JAK kinases to induce expression of antiviral effector genes. In the nematode C. elegans, which lacks the interferon system, the major antiviral response so far described is RNA interference but whether additional gene expression responses are employed is not known. Here we show that, despite the absence of both interferon and JAK, the C. elegans STAT homologue STA-1 orchestrates antiviral immunity. Intriguingly, mutants lacking STA-1 show increased resistance to antiviral infection. Using gene expression analysis and chromatin immunoprecipitation we show that, in contrast to the mammalian pathway, STA-1 acts as a transcriptional repressor. Thus STA-1 might act to suppress a constitutive antiviral response in the absence of infection. Using a reverse genetic screen we identify the SID-3 as a kinase upstream of STA-1 in the response to infection. Together, our work identifies a novel STAT regulatory cascade controlling its activity in antiviral resistance, illustrating the complex evolutionary trajectory displayed by innate immune signaling pathways across metazoan organisms.
