Acetylation of SUMO1 Alters Interactions with the SIMs of PML and Daxx in a Protein-Specific Manner

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Catalase, but not MnSOD, inhibits glucose deprivation-activated ASK1-MEK-MAPK signal transduction pathway and prevents relocalization of Daxx: hydrogen peroxide as a major second messenger of metabolic oxidative stress

Overexpression of catalase, but not manganese superoxide dismutase (MnSOD), inhibited glucose deprivation-induced cytotoxicity and c-Jun N-terminal kinase 1 (JNK1) activation in human prostate adenocarcinoma DU-145 cells. Suppression of JNK1 activation by catalase overexpression resulted from inhibition of apoptosis signal-regulating kinase 1 (ASK1) activation by preventing dissociation of thioredoxin (TRX) from ASK1. Overexpression of catalase also inhibited relocalization of Daxx from the nucleus to the cytoplasm as well as association of Daxx with ASK1 during glucose deprivation. Taken together, hydrogen peroxide (H(2)O(2)) rather than superoxide anion (O(2) (*-)) acts as a second messenger of metabolic oxidative stress to activate the ASK1-MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-mitogen-activated protein kinase (MAPK) signal transduction pathway.     

Daxx mediates activation-induced cell death in microglia by triggering MST1 signalling

Microglia, the resident macrophages of the mammalian central nervous system, migrate to sites of tissue damage or infection and become activated. Although the persistent secretion of inflammatory mediators by the activated cells contributes to the pathogenesis of various neurological disorders, most activated microglia eventually undergo apoptosis through the process of activation-induced cell death (AICD). The molecular mechanism of AICD, however, has remained unclear. Here, we show that Daxx and mammalian Ste20-like kinase-1 (MST1) mediate apoptosis elicited by interferon-γ (IFN-γ) in microglia. IFN-γ upregulated the expression of Daxx, which in turn mediated the homodimerization, activation, and nuclear translocation of MST1 and apoptosis in microglial cells. Depletion of Daxx or MST1 by RNA interference also attenuated IFN-γ-induced cell death in primary rat microglia. Furthermore, the extent of IFN-γ-induced death of microglia in the brain of MST1-null mice was significantly reduced compared with that apparent in wild-type mice. Our results thus highlight new functions of Daxx and MST1 that they are the key mediators of microglial cell death initiated by the proinflammatory cytokine IFN-γ.     

IFN-zeta/ limitin: a member of type I IFN with mild lympho-myelosuppression

Interferon (IFN)-Zeta/limitin has been considered as a novel type I IFN by the Nomenclature Committee of the International Society for Interferon and Cytokine Research. IFN-Zeta/limitin shows some sequence homology with IFN-alpha and IFN-beta, has a globular structure with five alpha-helices and four loops, and recognizes IFN-alpha/beta receptor. Although IFN-zeta/limitin displays antiviral, immunomodulatory, and antitumor effects, it has much less lympho-myelosuppressive activities than IFN-alpha. Treatment of cells with type I IFNs induces and/or activates a number of molecules, which regulate cell cycle and apoptosis. It is noteworthy that IFN-zeta/limitin activates the Tyk2-Daxx and Tyk2-Crk pathways weaker than IFN-alpha. Because experiments using antisense oligonucleotides have revealed their essential role in type I IFN-related suppression of lympho-hematopoiesis, little ability of IFN-zeta/limitin to activate the Tyk2-dependent signaling pathway may explain its uniquely narrow range of biological activities. Further analysis of structure-function relationship of type I IFNs will establish an engineered cytokine with useful features of IFN-zeta/limitin.     

Daxx通过上调caveolin-1的表达介导Ox-LDL诱导巨噬细胞胆固醇蓄积和凋亡

为探讨Daxx对氧化型低密度脂蛋白(oxidized low-density lipoprotein,Ox-LDL)诱导巨噬细胞胆固醇蓄积和凋亡的介导作用及其可能的分子机制,用高效液相色谱法检测细胞内胆固醇含量,油红O染色观察细胞内脂滴的形成情况,流式细胞术和吖啶橙/溴化乙锭(AO/EB)染色法研究Ox-LDL对细胞凋亡的影响,Real time RT-PCR检测细胞内Daxx mRNA的表达水平,Western blot检测caveolin-1蛋白的表达,用特异性siRNA沉默Daxx在RAW264.7 细胞中的表达．Ox-LDL上调Daxx mRNA和caveolin-1的表达、增加细胞内胆固醇含量、促使RAW264.7细胞凋亡,用特异性siRNA干扰Daxx在RAW264.7细胞中的表达能降低caveolin-1的表达、减少细胞内胆固醇含量、以及抑制细胞凋亡．上述结果表明,Daxx对Ox-LDL诱导RAW264.7巨噬细胞胆固醇蓄积和凋亡具有介导作用,这一作用可能与Daxx上调caveolin -1的表达有关．     

Daxx的转录抑制及激活调控功能

Daxx定位细胞核PODs,可在转录调控中行使转录抑制或转录激活双重功能.Daxx通过转位、化学修饰、染色体调节、直接与转录因子或转录相关蛋白相互作用等多种方式发挥转录调控作用.其中,Daxx通过转位,转录后化学修饰,染色体调节,与转录因子或转录相关蛋白相互作用行使转录抑制功能,但相关研究表明Daxx同样可通过与相关因子相互作用激活转录,但具体作用机制尚不清楚.