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ENPP1 (Ecto-nucleotide pyrophosphatase phosphodiesterase 1), a type II transmembrane glycoprotein, hydrolyzes ATP to produce AMP and diphosphate, thereby inhibiting bone mineralization. A recent study showed that ENPP1 also preferentially hydrolyzes 2′3′-cGAMP (cyclic GMP-AMP) but not its linkage isomer 3′3′-cGAMP, and negatively regulates the cGAS-STING pathway in the innate immune system. Here, we present the high-resolution crystal structures of ENPP1 in complex with 3′3′-cGAMP and the reaction intermediate pA(3′,5′)pG. The structures revealed that the adenine and guanine bases of the dinucleotides are recognized by nucleotide- and guanine-pockets, respectively. Furthermore, the structures indicate that 2′3′-cGAMP, but not 3′3′-cGAMP, binds to the active site in a conformation suitable for catalysis, thereby explaining the specific degradation of 2′3′-cGAMP by ENPP1. Our findings provide insights into how ENPP1 hydrolyzes both ATP and cGAMP to participate in the two distinct biological processes. Ecto-nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) is a type II transmembrane glycoprotein that hydrolyzes both ATP and cGAMP. Here the authors present the crystal structures of the extracellular domain of mouse ENPP1 in complex with 3′3′-cGAMP and the reaction intermediate pA(3′,5′)pG and discuss mechanistic implications.

The linear ubiquitin chain assembly complex (LUBAC) is a ubiquitin ligase composed of the Heme-oxidized IRP2 ubiquitin ligase-1L (HOIL-1L), HOIL-1L-interacting protein (HOIP), and Shank-associated RH domain interactor (SHARPIN) subunits. LUBAC specifically generates the N-terminal Met1-linked linear ubiquitin chain and regulates acquired and innate immune responses, such as the canonical nuclear factor-κB (NF-κB) and interferon antiviral pathways. Deubiquitinating enzymes, OTULIN and CYLD, physiologically bind to HOIP and control its function by hydrolyzing the linear ubiquitin chain. Moreover, proteins containing linear ubiquitin-specific binding domains, such as NF-κB-essential modulator (NEMO), optineurin, A20-binding inhibitors of NF-κB (ABINs), and A20, modulate the functions of LUBAC, and the dysregulation of the LUBAC-mediated linear ubiquitination pathway induces cancer and inflammatory, autoimmune, and neurodegenerative diseases. Therefore, inhibitors of LUBAC would be valuable to facilitate investigations of the molecular and cellular bases for LUBAC-mediated linear ubiquitination and signal transduction, and for potential therapeutic purposes. We identified and characterized α,β-unsaturated carbonyl-containing chemicals, named HOIPINs (HOIP inhibitors), as LUBAC inhibitors. We summarize recent advances in elucidations of the pathophysiological functions of LUBAC-mediated linear ubiquitination and identifications of its regulators, toward the development of LUBAC inhibitors.

Recent studies have shown that some people claim that their skin gases provoke allergy-like reactions in people in their near vicinity. Such a phenomenon or symptom is called ‘people allergic to me (PATM)’. Although numerous people suffer from PATM, the actual conditions are unknown. The aim of this study was to investigate the characteristics of human skin profiles in patients with PATM by measuring the dermal emission fluxes of 75 skin gases using passive flux sampler and gas chromatography/mass spectrometry. We found common features in the human skin gas profiles of 20 subjects with PATM, with a significant difference from those of 24 non-PATM subjects: greater emissions of petrochemicals, organosulfur compounds, and some aldehydes and lower emissions of aroma compounds and others. The ratio of toluene to benzaldehyde is considered a vital sign that suggests the fundamental of PATM. These findings indicate that PATM is a medically unexplained phenomenon or symptom worthy of further research, which requires an interdisciplinary approach.

Histamine, which is mainly produced by mast cells and basophils, participates in various allergic symptoms, and some studies have reported that macrophages also produce histamine. Moreover, recent studies have revealed that macrophages, especially alternatively activated macrophages (M2) induced by T helper 2 (Th2) cytokines, such as interleukin (IL)-4 and IL-13, participate in the pathogenesis of allergic diseases. The major source of Th2 cytokines is antigen-specific Th2 cells. To elucidate the relationship between histamine, macrophages, and Th2 cells in allergic inflammation, we established a macrophage-Th2 cell co-culture model in vitro and an antigen-specific Th2 cell transfer mouse model of rhinitis. In vitro analyses indicated that macrophages produce histamine by interacting with antigen-specific Th2 cells through the antigen. Furthermore, Th2 cells and macrophages cooperatively elicited rhinitis in the mouse model. We determined that histamine induces Th2- and macrophage-elicited sneezing responses through H1 receptor signaling, whereas it induces nasal eosinophil infiltrations through H4 receptor signaling. Collectively, these results indicate a novel histamine production mechanism by macrophages, in which Th2 cells and macrophages cooperatively induce nasal allergic inflammation through histamine signaling.

Deubiquitinating enzymes (DUBs) regulate numerous cellular functions by removing ubiquitin modifications. We examined the effects of 88 human DUBs on linear ubiquitin chain assembly complex (LUBAC)-induced NF-κB activation, and identified OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-κB pathway by hydrolyzing K63-linked ubiquitin chains from NF-κB signaling factors, including LUBAC. OTUD1 negatively regulates the canonical NF-κB activation, apoptosis, and necroptosis, whereas OTUD1 upregulates the interferon (IFN) antiviral pathway. Mass spectrometric analysis showed that OTUD1 binds KEAP1, and the N-terminal intrinsically disordered region of OTUD1, which contains an ETGE motif, is indispensable for the KEAP1-binding. Indeed, OTUD1 is involved in the KEAP1-mediated antioxidant response and reactive oxygen species (ROS)-induced cell death, oxeiptosis. In Otud1 −/− -mice, inflammation, oxidative damage, and cell death were enhanced in inflammatory bowel disease, acute hepatitis, and sepsis models. Thus, OTUD1 is a crucial regulator for the inflammatory, innate immune, and oxidative stress responses and ROS-associated cell death pathways.

Type I interferon (IFN) plays a crucial role in innate and adaptive immunity, and aberrant IFN responses are involved in systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) and dermatomyositis (DM). Type I IFNs can be induced by transcribed retrotransposons. The regulation of retrotransposons and type I IFN and the downstream IFN pathways in SLE, DM, and autoimmune blistering disease (AIBD) were investigated. The gene expression levels of retrotransposons, including LINE-1 , type I-III IFNs, and IFN-stimulated genes (ISGs) in peripheral blood cells from patients with DM (n = 24), SLE (n = 19), AIBD (n = 14) and healthy controls (HCs, n = 10) were assessed by quantitative polymerase chain reaction. Upregulation of retrotransposons and IFNs was detected in DM patient samples, as is characteristic, compared to HCs; however, ISGs were not uniformly upregulated. In contrast, retrotransposons and IFNs, except for type II IFN, such as IFN-γ, were not upregulated in SLE. In AIBD, only some retrotransposons and type I interferons were upregulated. The DM, SLE, and AIBD samples showed coordinated expression of retrotransposons and type I IFNs and distinct spectra of IFN signaling. A positive correlation between LINE-1 and IFN-β1 was also detected in human cell lines. These factors may participate in the development of these autoimmune diseases.

Age-related macular degeneration (AMD) is the leading sight-threatening disease in developed countries. On the other hand, recent studies indicated an ethnic variation in the phenotype of AMD. For example, several reports demonstrated that the incidence of drusen in AMD patients is less in Asians compared to Caucasians though the reason has not been clarified yet. In the last decades, several genome association studies have disclosed many susceptible genes of AMD and revealed that the association strength of some genes was different among races and AMD phenotypes. In this review article, the essential findings of the clinical studies and genome association studies for the most significant genes CFH and ARMS2/HTRA1 in AMD of different races are summarized, and theoretical hypotheses about the molecular mechanisms underlying the ethnic variation in the AMD manifestation mainly focused on those genes between Caucasians and Asians are discussed.

Optineurin ( OPTN) mutations cause neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and glaucoma. Although the ALS-associated E478G mutation in the UBAN domain of OPTN reportedly abolishes its NF-κB suppressive activity, the precise molecular basis in ALS pathogenesis still remains unclear. Here we report that the OPTN-UBAN domain is crucial for NF-κB suppression. Our crystal structure analysis reveals that OPTN-UBAN binds linear ubiquitin with homology to NEMO. TNF-α-mediated NF-κB activation is enhanced in OPTN -knockout cells, through increased ubiquitination and association of TNF receptor (TNFR) complex I components. Furthermore, OPTN binds caspase 8, and OPTN deficiency accelerates TNF-α-induced apoptosis by enhancing complex II formation. Immunohistochemical analyses of motor neurons from OPTN-associated ALS patients reveal that linear ubiquitin and activated NF-κB are partially co-localized with cytoplasmic inclusions, and that activation of caspases is elevated. Taken together, OPTN regulates both NF-κB activation and apoptosis via linear ubiquitin binding, and the loss of this ability may lead to ALS. Mutations in optineurin are associated with neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, the authors report the structure of the ubiquitin binding domain of optineurin, which binds linear ubiquitin with homology to NEMO, and explore the function of this domain.

Protein ubiquitination, which is catalyzed by ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin ligases, is a crucial post-translational modification to regulate numerous cellular functions in a spatio–temporal-specific manner. The human genome encodes ~100 deubiquitinating enzymes (DUBs), which antagonistically regulate the ubiquitin system. OTUD1, an ovarian tumor protease (OTU) family DUB, has an N-terminal-disordered alanine-, proline-, glycine-rich region (APGR), a catalytic OTU domain, and a ubiquitin-interacting motif (UIM). OTUD1 preferentially hydrolyzes lysine-63-linked ubiquitin chains in vitro; however, recent studies indicate that OTUD1 cleaves various ubiquitin linkages, and is involved in the regulation of multiple cellular functions. Thus, OTUD1 predominantly functions as a tumor suppressor by targeting p53, SMAD7, PTEN, AKT, IREB2, YAP, MCL1, and AIF. Furthermore, OTUD1 regulates antiviral signaling, innate and acquired immune responses, and cell death pathways. Similar to Nrf2, OTUD1 contains a KEAP1-binding ETGE motif in its APGR and regulates the reactive oxygen species (ROS)-mediated oxidative stress response and cell death. Importantly, in addition to its association with various cancers, including multiple myeloma, OTUD1 is involved in acute graft-versus-host disease and autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and ulcerative colitis. Thus, OTUD1 is an important DUB as a therapeutic target for a variety of diseases.

Objective Histamine derived from mast cells and basophils plays important roles in inducing allergic symptoms. Although T cells also produce histamine, the involvement of the histamine produced from T cells has remained enigmatic. We sought to reveal the roles of T helper 2 (Th2) cell-derived histamine in nasal allergic disorders. Methods The histamine production from Th2 cells was measured by EIA. The mRNA expression of histidine decarboxylase (HDC) was measured by real-time PCR. To investigate the roles of Th2 cell-derived histamine in vivo, we analyzed an antigen-specific Th2 cell transfer mouse model. Results Th2 cells produced histamine by T cell receptor stimulation, and these properties were specific for Th2 cells, but not Th1 cells and naïve CD4 T cells. The histamine produced from Th2 cells was involved in the infiltrations of Th2 cells in response to antigen exposure. Conclusion These results suggest that Th2 cell-derived histamine play important roles in nasal allergic disorders.