去泛素化酶USP29调控CBX6蛋白质稳定性

Deubiquitinating Enzyme USP29 Regulates the Protein Stability of CBX6

多梳家族(polycomb group,PcG)是一类控制细胞命运和胚胎发育的转录抑制因子,主要以转录抑制复合物(polycomb repressive complex,PRC)的形式发挥功能。染色体盒蛋白质同源物6(chromobox protein homolog 6,CBX6)是PRC1的核心蛋白质亚基之一,在基因表达调控、细胞更新分化、肿瘤发生发展和干细胞干性维持等方面发挥重要的作用。本研究发现,CBX6通过泛素-蛋白酶体依赖性途径降解,接着利用包含92个去泛素化酶(deubiquitinating enzyme,DUB)基因表达文库进行筛选,发现泛素特异性蛋白酶29(ubiquitin-specific protease,USP29)能够明显地稳定CBX6的蛋白质水平并延长其半衰期(P<0.05);免疫沉淀结果发现,CBX6通过其C-端结构域与USP29发生相互作用;进一步研究发现,USP29通过去泛素化CBX6调控CBX6蛋白质稳定性,且这个过程依赖于USP29本身去泛素化酶活性。细胞增殖结果还发现,USP29能抑制MCF7细胞的增殖(P<0.0001)。综上所述,本研究通过筛选发现,USP29能够通过去泛素化CBX6来稳定CBX6蛋白质水平,且USP29能够抑制MCF7细胞增殖进程。

Polycomb group(PcG)proteins are transcriptional repressors that control cell fate and the development of embryo,and they elicit function mainly in the form of polycomb repressive complex(PRC).Chromobox protein homolog 6(CBX6)is one of the core protein subunits of PRC1,which plays an important role in gene expression regulation,cell renewal and differentiation,tumorigenesis and development,and stem cell maintenance.In this study,CBX6 was found to be degraded through a ubiquitin-proteasome dependent pathway.Then the gene expression library containing 92 deubiquitinating enzymes(DUB)was used to screen DUB targeting CBX6 and results found that ubiquitin-specific protease 29(USP29)could obviously stabilize CBX6 protein level and extend its half-life(P<0.05).Immunoprecipitation experiments found that CBX6 interacted with USP29 through its C-terminal domains;Further studies found that USP29 regulated the protein stability of CBX6 by deubiquitination in an enzymatic-activity dependent manner.Cell proliferation assay also found that USP29 inhibited the proliferation of MCF7 cells(P<0.0001).Taken together,through screening,this study found that USP29 could stabilize CBX6 protein level through deubiquitinating CBX6 and inhibit the cell proliferation of MCF7.