The type I alpha/beta interferons (IFN-␣/␤) are known to play an important role in host defense against influenza A virus infection, but we have now discovered that the recently identified type III IFNs (IFN-) constitute the major response to intranasal infection with this virus. Type III IFNs were present at much higher levels than type I IFNs in the lungs of infected mice, and the enhanced susceptibility of STAT2 ؊/؊ animals demonstrated that only signaling through the IFN-␣/␤ or IFN-pathways was sufficient to mediate protection. This finding offers a possible explanation for the similar levels of antiviral protection found in wild-type (WT) mice and in animals lacking a functional type I IFN receptor (IFNAR ؊/؊ ) but also argues that our current understanding of type III IFN induction is incomplete. While murine IFN-production is thought to depend on signaling through the type I IFN receptor, we demonstrate that intranasal influenza A virus infection leads to the robust type III IFN induction in the lungs of both WT and IFNAR ؊/؊ mice. This is consistent with previous studies showing that IFNAR-mediated protection is redundant for mucosal influenza virus infection and with data showing that the type III IFN receptor is expressed primarily by epithelial cells. However, the overlapping effects of these two cytokine families are limited by their differential receptor expression, with a requirement for IFN-␣/␤ signaling in combating systemic disease.Type I interferons (IFNs) were first recognized for their ability to interfere with influenza virus replication (31) and are now recognized as an early and powerful host defense against virus infection. In all cell types that have been investigated, virus infection results in the synthesis and secretion of the type I alpha/beta interferons (IFN-␣/␤). Once secreted, IFN-␣/␤ acts in an autocrine or paracrine manner by binding the ubiquitously expressed IFN-␣/␤ receptor (IFNAR). Receptor binding activates the Jak-STAT signaling cascade leading to transcriptional upregulation of the IFN-stimulated genes which mediate the biological effects of IFN (10,18).IFN induction by influenza A virus involves recognition of viral components by both cytoplasmic receptors and TLR7, although the precise mechanism used depends upon the infected cell type. In fibroblasts, epithelial cells, and conventional dendritic cells (cDCs), IFN-␤ gene expression is largely dependent upon virus activation of the RNA helicase retinoic acid-induced gene I (RIG-I) (26), with the subsequent phosphorylation of IFN regulatory factor 3 (IRF3) by IB kinase ε (IKKε)/TANK-binding kinase 1 (TBK1). Once IFN-␤ (as well as IFN-␣4 in mouse) has been synthesized and secreted, signaling through the Jak-STAT pathway upregulates production of IRF7, which then mediates the transcription of additional 33,45). In this way, an amplification pathway is established wherein early, IRF3-mediated production of IFN-␤ promotes the synthesis of multiple IFN-␣ subtypes.Type III IFNs were very recently discovered and are designated ...

The TREX1 gene encodes a potent DNA exonuclease, and mutations in TREX1 cause a spectrum of lupus-like autoimmune diseases. Most lupus patients develop autoantibodies to double-stranded DNA (dsDNA), but the source of DNA antigen is unknown. The TREX1 D18N mutation causes a monogenic, cutaneous form of lupus called familial chilblain lupus, and the TREX1 D18N enzyme exhibits dysfunctional dsDNA-degrading activity, providing a link between dsDNA degradation and nucleic acid-mediated autoimmune disease. We determined the structure of the TREX1 D18N protein in complex with dsDNA, revealing how this exonuclease uses a novel DNA-unwinding mechanism to separate the polynucleotide strands for single-stranded DNA (ssDNA) loading into the active site. The TREX1 D18N dsDNA interactions coupled with catalytic deficiency explain how this mutant nuclease prevents dsDNA degradation. We tested the effects of TREX1 D18N in vivo by replacing the TREX1 WT gene in mice with the TREX1 D18N allele. The TREX1 D18N mice exhibit systemic inflammation, lymphoid hyperplasia, vasculitis, and kidney disease. The observed lupus-like inflammatory disease is associated with immune activation, production of autoantibodies to dsDNA, and deposition of immune complexes in the kidney. Thus, dysfunctional dsDNA degradation by TREX1 D18N induces disease in mice that recapitulates many characteristics of human lupus. Failure to clear DNA has long been linked to lupus in humans, and these data point to dsDNA as a key substrate for TREX1 and a major antigen source in mice with dysfunctional TREX1 enzyme.

SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO−TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.