Stuxnet Facilitates the Degradation of Polycomb Protein during Development.
Polycomb-group (PcG) proteins function to ensure correct deployment of developmental programs by epigenetically repressing target gene expression. Despite the importance, few studies have been focused on the regulation of PcG activity itself. Here, we report a Drosophila gene, stuxnet (stx), that controls Pc protein stability. We find that heightened stx activity leads to homeotic transformation, reduced Pc activity, and de-repression of PcG targets. Conversely, stx mutants, which can be rescued by decreased Pc expression, display developmental defects resembling hyperactivation of Pc. Our biochemical analyses provide a mechanistic basis for the interaction between stx and Pc; Stx facilitates Pc degradation in the proteasome, independent of ubiquitin modification. Furthermore, this mode of regulation is conserved in vertebrates. Mouse stx promotes degradation of Cbx4, an orthologous Pc protein, in vertebrate cells and induces homeotic transformation in Drosophila. Our results highlight an evolutionarily conserved mechanism of regulated protein degradation on PcG homeostasis and epigenetic activity.
State Key Laboratory of Membrane Biology, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
Juan
J
Du
State Key Laboratory of Membrane Biology, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
Junzheng
J
Zhang
State Key Laboratory of Membrane Biology, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing 100871, China.
Tao
T
He
State Key Laboratory of Membrane Biology, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing 100871, China.
Yajuan
Y
Li
State Key Laboratory of Membrane Biology, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing 100871, China.
Ying
Y
Su
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Feng
F
Tie
State Key Laboratory of Membrane Biology, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
Min
M
Liu
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Peter J
PJ
Harte
State Key Laboratory of Membrane Biology, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China. Electronic address: zhua@pku.edu.cn.
Alan Jian
AJ
Zhu
D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000254:growth & development* / Q000378:metabolism*; D004843:Epistasis, Genetic; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D059748:Proteolysis; D013329:Structure-Activity Relationship; D054875:Ubiquitination; D014714:Vertebrates / Q000378:metabolism
D029721:Drosophila Proteins; C066770:Pc protein, Drosophila; C000620279:Stx protein, Drosophila; D063150:Polycomb Repressive Complex 1; D046988:Proteasome Endopeptidase Complex