Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability

Chronic environmental exposure to metal toxicants such as chromium and arsenic is closely related to the development of several types of common cancers. Genetic and epigenetic studies in the past decade reveal that post-translational modifications of histones play a role in metal carcinogenesis. However, exact molecular mechanisms of metal carcinogenesis remain to be elucidated. In this study we found that As₂O₃, an environmental metal toxicant, upregulated overall modifications of many cellular proteins by SUMO2/3. Sumoylated proteins from arsenic-treated cells constitutively expressing His₆-SUMO2 were pulled down by Ni-IDA resin under denaturing conditions. Mass spectrometric analysis revealed over 100 proteins that were potentially modified by sumoylation. Mus81, a DNA endonuclease involved in homologous recombination repair, was among the identified proteins whose sumoylation was increased after treatment with As₂O_3. We further showed that K10 and K524 were 2 lysine residues essential for Mus81 sumoylation. Moreover, we demonstrated that Mus81 sumoylation is important for normal mitotic chromosome congression and that cells expressing SUMO-resistant Mus81 mutants displayed compromised DNA damage responses after exposure to metal toxins such as Cr(VI) and arsenic.     

Trophic factor BDNF inhibits GABAergic signaling by facilitating dendritic enrichment of SUMO E3 ligase PIAS3 and altering gephyrin scaffold

Posttranslational addition of a small ubiquitin-like modifier (SUMO) moiety (SUMOylation) has been implicated in pathologies such as brain ischemia, diabetic peripheral neuropathy, and neurodegeneration. However, nuclear enrichment of SUMO pathway proteins has made it difficult to ascertain how ion channels, proteins that are typically localized to and function at the plasma membrane, and mitochondria are SUMOylated. Here, we report that the trophic factor, brain-derived neurotrophic factor (BDNF) regulates SUMO proteins both spatially and temporally in neurons. We show that BDNF signaling via the receptor tropomyosin-related kinase B facilitates nuclear exodus of SUMO proteins and subsequent enrichment within dendrites. Of the various SUMO E3 ligases, we found that PIAS-3 dendrite enrichment in response to BDNF signaling specifically modulates subsequent ERK1/2 kinase pathway signaling. In addition, we found the PIAS-3 RING and Ser/Thr domains, albeit in opposing manners, functionally inhibit GABA-mediated inhibition. Finally, using oxygen–glucose deprivation as an in vitro model for ischemia, we show that BDNF–tropomyosin-related kinase B signaling negatively impairs clustering of the main scaffolding protein at GABAergic postsynapse, gephyrin, whereby reducing GABAergic neurotransmission postischemia. SUMOylation-defective gephyrin K148R/K724R mutant transgene expression reversed these ischemia-induced changes in gephyrin cluster density. Taken together, these data suggest that BDNF signaling facilitates the temporal relocation of nuclear-enriched SUMO proteins to dendrites to influence postsynaptic protein SUMOylation.     

拟南芥SUMO底物的研究进展

SUMO(Small ubiquitin-related modifier)化修饰是普遍存在于真核生物中的一种翻译后修饰, 在很多细胞过程中发挥重要作用。文章阐述了拟南芥中SUMO底物的最新研究进展。首先介绍SUMO化修饰过程, SUMO底物的鉴定, 包括鉴定方法的进展和鉴定成果。然后依据底物的亚细胞定位、生理功能和参与的生理生化过程对其进行分类和分析, 以期更好地理解蛋白质SUMO化修饰方式在植物生长发育中的功能。     

蛋白质修饰对Wnt信号通路的调控

Wnt信号通路与细胞的生长发育和分化等密切相关,是细胞中重要的信号转导途径,在 多种癌症中,都有该通路的异常改变.Wnt信号通路主要是通过一系列蛋白将Wnt信号传导至β连环蛋白（β-catenin,β-cat）,使后者入核并与转录因子T细胞因子/淋巴细胞增 强因子（T cell factor / lymphoid enhancer factor,TCF/LEF）结合,从而促进下游基因的转录,进而调控细胞的多种生理过程.在该通路中,涉及轴蛋白（Axin）、结肠腺瘤样息 肉病蛋白(adenomatous polyposis coli,APC)、糖原合酶激酶3β (glycogen synthase kinase-3β, GSK-3β)、β连环蛋白和酪蛋白激酶I (casein kinase I,CKI)等众多调节因子,这些因子能发生多种化学修饰,如磷酸化、泛素化（ubiquitylation）、苏素化 (small ubiquitin related moditier,SUMO)和乙酰化等,从而影响β连环蛋白、T细胞因子的稳定性、细胞定位以及活性,最终起到调节Wnt信号通路的作用.     

Directing p53 to induce autophagy

Comment on: Naidu SR, et al. Cell Cycle 2012; 11:2717-28.     

Sumoylation of eIF4E activates mRNA translation

Eukaryotic translation initiation factor 4E (eIF4E) is the cap‐binding protein that binds the 5′ cap structure of cellular messenger RNAs (mRNAs). Despite the obligatory role of eIF4E in cap‐dependent mRNA translation, how the translation activity of eIF4E is controlled remains largely undefined. Here, we report that mammalian eIF4E is regulated by SUMO1 (small ubiquitin‐related modifier 1) conjugation. eIF4E sumoylation promotes the formation of the active eIF4F translation initiation complex and induces the translation of a subset of proteins that are essential for cell proliferation and preventing apoptosis. Furthermore, disruption of eIF4E sumoylation inhibits eIF4E‐dependent protein translation and abrogates the oncogenic and antiapoptotic functions associated with eIF4E. These data indicate that sumoylation is a new fundamental regulatory mechanism of protein synthesis. Our findings suggest further that eIF4E sumoylation might be important in promoting human cancers.