BST2 inhibits type I IFN (interferon) signaling by accelerating MAVS degradation through CALCOCO2-directed autophagy

Macroautophagy/autophagy is a conserved lysosomal degradation system that breaks down intracellular material through the formation of double-membrane autophagosomes in eukaryotic cells. Cargo receptors have been shown to play essential roles in capturing and delivering specific substrates into phagophores, the precursors to autophagosomes, for degradation. However, the detailed mechanism underlying selective recognition of the substrates for autophagic degradation remains poorly understood. Recently, we have revealed that IFN (interferon)-induced BST2 recruits the E3 ubiquitin ligase MARCH8 to catalyze the K27-linked ubiquitination of MAVS for CALCOCO2-directed autophagic degradation, hence inhibiting DDX58-mediated type I interferon signaling through a negative feedback loop.     

Interferon alpha induces cell death through interference with interleukin 6 signaling and inhibition of STAT3 activity

In multiple myeloma, which commonly depends on interleukin 6, IL-6, survival signaling induced by this cytokine is largely mediated by activation of STAT3. Interferon alpha (IFNalpha) treatment of cell lines derived from multiple myeloma or of myeloma tumor cells ex vivo leads to apoptosis. In this study we demonstrate that IFNalpha treatment of the two myeloma cell lines, U266-1984 and U-1958, results in the decrease of STAT3 activity as demonstrated by a diminished STAT3/3 DNA-binding activity and the shift from STAT3/3 towards STAT1/1 and STAT3/1 complexes in EMSA, leading to the down-regulation of known STAT3 target genes such as Bcl-X(L), Mcl-1 and survivin. Ectopic expression of a form of STAT3, STAT3C, rescued U266-1984 cells from IFNalpha-induced apoptosis. IFNalpha promoted sustained accumulation of tyrosine phosphorylated STAT3C in the nucleus and a prolonged DNA binding of the STAT3/3 homodimers in EMSA. The shift towards a sustained STAT3 response in IFNalpha-treated STAT3C-transfected cells led to a hyper-induction of Bcl-2 and Mcl-1 proteins. Thus our data demonstrated that IFNalpha is able to interfere with IL-6 signaling by inhibiting STAT3 activity and that the abrogation of STAT3 activity accounts for the ability of IFNalpha to induce apoptosis in myeloma cells.     

The IL-6 family of cytokines modulates STAT3 activation by desumoylation of PML through SENP1 induction

Post-translational modification by small ubiquitin-like modifier (SUMO) plays an important role in the regulation of different signaling pathways and is involved in the formation of promyelocytic leukemia (PML) protein nuclear bodies following sumoylation of PML. In the present study, we found that IL-6 induces desumoylation of PML and dissociation between PML and SUMO1 in hepatoma cells. We also found that IL-6 induces mRNA expression of SENP1, a member of the SUMO-specific protease family. Furthermore, wild-type SENP1 but not an inactive SENP1 mutant restored the PML-mediated suppression of STAT3 activation. These results indicate that the IL-6 family of cytokines modulates STAT3 activation by desumoylation and inactivation PML through SENP1 induction.     

In vitro inhibitory effects of cirsiliol on IL-6-induced STAT3 activation through anti-inflammatory activity

Many studies have identified and described various medicinal effects of cirsiliol. Here, we investigated the signaling pathway involved in the anti-inflammatory effects of cirsiliol on IL-6-induced activity. Cirsiliol showed no cytotoxicity and inhibited pSTAT3-induced luciferase activity. At the molecular level, cirsiliol suppressed the expression of IL-6-induced inflammatory marker genes such as CRP, IL-1β, ICAM-1 and SOCS3, IL-6-induced activation of Jak2, gp130, STAT3 and ERK and nuclear translocation of STAT3, as measured by PCR, immunofluorescence staining and western blot analysis. However, the interaction between IL-6 and its receptor was not affected by cirsiliol treatment. These results indicate that cirsiliol attenuates IL-6-induced cellular signaling by regulating Jak2 phosphorylation. Therefore, cirsiliol could be a therapeutic agent for IL-6-related inflammatory diseases.     

CD95/Fas Increases Stemness in Cancer Cells by Inducing a STAT1-Dependent Type I Interferon Response

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Prostaglandin E2 down-regulation of cytochrome P-450 2B1 expression induced by phenobarbital is through EP2 receptor in rat hepatocytes

Cytochrome P-450 is an important bioactivation-detoxification system in vivo. Its expression is regulated by foreign chemicals and dietary factors, and lipids have been found to regulate its gene expression. We showed previously that prostaglandin E(2) (PGE(2)), a fatty acid metabolite, down-regulates cytochrome P-450 2B1 (CYP 2B1) expression induced by phenobarbital. The objective of the present study was to determine whether PGE(2) type 2 receptor (EP(2))-which is coupled to Gs-protein when bound by PGE(2), leading to cAMP production-is involved in this down-regulation. We also determined the possible roles of EP(2) downstream pathways in this down-regulation. We used a primary rat hepatocyte culture model in which EP(2) was shown to be present to study this question. The intracellular cAMP concentration in primary rat hepatocytes was significantly higher after treatment with 1microM PGE(2) than after treatment with 0, 0.01, or 0.1microM PGE(2). Butaprost, an EP(2) agonist, down-regulated CYP 2B1 expression in a dose-dependent manner. SQ22536, an adenylate cyclase inhibitor, reversed the down-regulation by PGE(2) as did H-89, a protein kinase A inhibitor. These results suggest that EP(2) and the downstream pathways of cAMP and protein kinase A are involved in the down-regulation of CYP 2B1 expression by PGE(2) in the presence of phenobarbital.     

SERP1 prevents hypoxia-reoxygenation-induced H9c2 apoptosis through activating JAK2/STAT3 pathway-dependent attenuation of endoplasmic reticulum stress

The endoplasmic reticulum (ER) stress plays an important role in myocardial ischemia/reperfusion (MI/R) injury. SERP1, the stress-associated endoplasmic reticulum protein 1, is involved in regulating ER stress response. However, whether it associates with MI/R injury is not identified. Here, we show that SERP1 is induced in the mouse heart after MI/R injury as well as in H9c2 cells under hypoxia/reoxygenation (H/R) treatment. Additionally, SERP1 overexpression reduces H/R-induced H9c2 apoptosis. Moreover, SERP1 overexpression suppresses H/R-induced ER stress and activates JAK2/STAT3 pathway. Furthermore, JAK2/STAT3 pathway inhibition by the specific inhibitor JSI-124 minimizes the suppressive effect of SERP1 overexpression on H/R-induced ER stress and H9c2 apoptosis. Together, these results uncover the protection of SERP1 against H/R-induced H9c2 apoptosis and further relate it to JAK2/STAT3 pathway-dependent attenuation of ER stress. This study suggests SERP1 as a potential regulator invovled in the pathophysiology of MI/R injury.