Autophagy induction via STING trafficking is a primordial function of the cGAS pathway.

Cyclic GMP-AMP (cGAMP) synthase (cGAS) detects infections or tissue damage by binding to microbial or self DNA in the cytoplasm1. Upon binding DNA, cGAS produces cGAMP that binds to and activates the adaptor protein STING, which then activates the kinases IKK and TBK1 to induce interferons and other cytokines2-6. Here we report that STING also activates autophagy through a mechanism that is independent of TBK1 activation and interferon induction. Upon binding cGAMP, STING translocates to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) and the Golgi in a process that is dependent on the COP-II complex and ARF GTPases. STING-containing ERGIC serves as a membrane source for LC3 lipidation, which is a key step in autophagosome biogenesis. cGAMP induced LC3 lipidation through a pathway that is dependent on WIPI2 and ATG5 but independent of the ULK and VPS34-beclin kinase complexes. Furthermore, we show that cGAMP-induced autophagy is important for the clearance of DNA and viruses in the cytosol. Interestingly, STING from the sea anemone Nematostella vectensis induces autophagy but not interferons in response to stimulation by cGAMP, which suggests that induction of autophagy is a primordial function of the cGAS-STING pathway.

IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens.

Interleukin 17 receptor E (IL-17RE) is an orphan receptor of the IL-17 receptor family. Here we show that IL-17RE is a receptor specific to IL-17C and has an essential role in host mucosal defense against infection. IL-17C activated downstream signaling through IL-17RE-IL-17RA complex for the induction of genes encoding antibacterial peptides as well as proinflammatory molecules. IL-17C was upregulated in colon epithelial cells during infection with Citrobacter rodentium and acted in synergy with IL-22 to induce the expression of antibacterial peptides in colon epithelial cells. Loss of IL-17C-mediated signaling in IL-17RE-deficient mice led to lower expression of genes encoding antibacterial molecules, greater bacterial burden and early mortality during infection. Together our data identify IL-17RE as a receptor of IL-17C that regulates early innate immunity to intestinal pathogens.

Human plasma cells express granzyme B.

While studying the plasma cell (PC) compartment in human tonsils, we identified that immunoglobulin kappa or lambda chain-expressing PCs are the main cells expressing granzyme B (GrzB). In vitro studies revealed that activated B cells differentiated into GrzB-expressing PCs when co-cultured with macrophages and follicular helper T cells. This effect could be reproduced on combined stimulation of IL-15 (produced by macrophages) and IL-21 (produced by T follicular helper cells) in a STAT3-dependent manner. Whereas IL-21 triggers the transcription of mRNA of GrzB, IL-15 synergizes the translation of GrzB proteins. The precise role of GrzB in PC biology remains to be understood and studies in mice will not help as their PCs do not express GrzB.

[Expression of cyclooxygenase-2 in bladder transitional cell carcinoma and the significance thereof].

OBJECTIVE: To study the expression of cyclooxygenase-2 (COX-2) in bladder transitional cell carcinoma (Tcc) and the clinical significance thereof. METHODS: Immunohistochemistry was used to detect the expression of COX-2 in 56 specimens of bladder Tcc and 10 specimens of normal bladder tissue, all resected during operation. RESULTS: No expression of COX-2 was detected in the 10 specimens of normal bladder tissue and in the 56 specimens of bladder Tcc the positive rate of COX-2 was 55.36%. The expression of COX-2 in bladder Tcc was closely correlated with the grade and stage of tumor (both P < 0.01). CONCLUSION: COX-2 expression in bladder Tcc is closely correlated with the grade and stage.

NFATC3 promotes IRF7 transcriptional activity in plasmacy--toid dendritic cells.

Plasmacytoid dendritic cells (pDCs) rapidly produce large amounts of type 1 interferon (IFN) after Toll-like receptor 7 and 9 engagements. This specialized function of type 1 IFN production is directly linked to the constitutive expression of IRF7, the master transcription factor for type 1 IFN production. However, the IRF7 regulatory network in pDCs remains largely unknown. In this study, we identify that the transcription factor NFATC3 specifically binds to IRF7 and enhances IRF7-mediated IFN production. Furthermore, knockout of NFATC3 greatly reduced the CpG DNA-induced nuclear translocation of IRF7, which resulted in impaired type 1 IFN production in vitro and in vivo. In addition, we found that NFATC3 and IRF7 both bound to type 1 IFN promoters and that the NFAT binding site in IFN promoters was required for IRF7-mediated IFN expression. Collectively, our study shows that the transcription factor NFATC3 binds to IRF7 and functions synergistically to enhance IRF7-mediated IFN expression in pDCs.

Solitary fibrous tumors of the prostate: A case report.

Increasing numbers of extrapleural solitary fibrous tumours (SFTs), including the prostate SFT, have been reported over the last 10-years. Prostate SFT is relatively uncommon, with <20 cases reported in the literature worldwide. In the present study, a prostate SFT case, which was initially misdiagnosed as benign prostatic hyperplasia, is presented. The patient was subjected to three surgeries (cystoscopy and per urethra lithocystotomy, transurethral resection of the prostate and nerve-sparing retropubic radical prostatectomy) prior to SFT diagnosis. It was demonstrated that histopathological and immunohistochemical factors (positive staining for CD34 and B cell lyphoma-2 expression) were of significant diagnostic value. Thus, nerve-sparing retropubic radical prostatectomy for total resection may be the best therapeutic strategy to treat prostate SFT, allowing the preservation of sexual function and reducing the risk of locoregional recurrence.

TRAF6-dependent Act1 phosphorylation by the IκB kinase-related kinases suppresses interleukin-17-induced NF-κB activation.

Interleukin-17 (IL-17) is critically involved in the pathogenesis of various inflammatory disorders. IL-17 receptor (IL-17R)-proximal signaling complex (IL-17R-Act1-TRAF6) is essential for IL-17-mediated NF-κB activation, while IL-17-mediated mRNA stability is TRAF6 independent. Recently, inducible IκB kinase (IKKi) has been shown to phosphorylate Act1 on Ser 311 to mediate IL-17-induced mRNA stability. Here we show that TANK binding kinase 1 (TBK1), the other IKK-related kinase, directly phosphorylated Act1 on three other Ser sites to suppress IL-17R-mediated NF-κB activation. IL-17 stimulation activated TBK1 and induced its association with Act1. IKKi also phosphorylated Act1 on the three serine sites and played a redundant role with TBK1 in suppressing IL-17-induced NF-κB activation. Act1 phosphorylation on the three sites inhibited its association with TRAF6 and consequently NF-κB activation in IL-17R signaling. Interestingly, TRAF6, but not TRAF3, which is the upstream adaptor of the IKK-related kinases in antiviral signaling, was critical for IL-17-induced Act1 phosphorylation. TRAF6 was essential for IL-17-induced TBK1 activation, its association with Act1, and consequent Act1 phosphorylation. Our findings define a new role for the IKK-related kinases in suppressing IL-17-mediated NF-κB activation through TRAF6-dependent Act1 phosphorylation.

Persistent stimulation with interleukin-17 desensitizes cells through SCFß-TrCP-mediated degradation of Act1.

The proinflammatory cytokine interleukin-17 (IL-17) is important for the immune response to pathogens and also contributes to the pathogenesis of various inflammatory diseases. To avoid persistent inflammation, signaling by the IL-17 receptor (IL-17R), which involves the adaptor protein Act1, must be tightly controlled. Here, we report that persistent stimulation of HeLa cells with IL-17 resulted in degradation of Act1 and desensitization of IL-17R signaling. IL-17 stimulated the Lys48-linked polyubiquitination and degradation of Act1, which was phosphorylation-dependent, similar to the IL-17-dependent degradation of inhibitor of nuclear factor κB α. Act1 was recruited to SCF (Skp1-cullin-1-F-box)-type E3 ubiquitin ligase complexes containing ß-transducin repeat-containing protein 1 (ß-TrCP1) or ß-TrCP2 in a phosphorylation-dependent manner upon stimulation of cells with IL-17. Dominant-negative ß-TrCP or knockdown of ß-TrCP1 and ß-TrCP2 markedly reduced IL-17-induced, phosphorylation-dependent ubiquitination and degradation of Act1. Thus, our studies identify a previously uncharacterized desensitization mechanism, involving the SCFß-TrCP-mediated degradation of Act1, that occurs during persistent stimulation with IL-17.

Modulation of experimental autoimmune encephalomyelitis through TRAF3-mediated suppression of interleukin 17 receptor signaling.

Interleukin 17 (IL-17) plays critical roles in the pathogenesis of various autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE). How the signals triggered by this powerful inflammatory cytokine are controlled to avoid abnormal inflammatory responses is not well understood. In this study, we report that TRAF3 is a receptor proximal negative regulator of IL-17 receptor (IL-17R) signaling. TRAF3 greatly suppressed IL-17-induced NF-κB and mitogen-activated protein kinase activation and subsequent production of inflammatory cytokines and chemokines. Mechanistically, the binding of TRAF3 to IL-17R interfered with the formation of the receptor signaling activation complex IL-17R-Act1-TRAF6, resulting in suppression of downstream signaling. TRAF3 markedly inhibited IL-17-induced expression of inflammatory cytokine and chemokine genes in vivo and consequently delayed the onset and greatly reduced the incidence and severity of EAE. Thus, TRAF3 is a negative regulator of IL-17R proximal signaling.