title: Protein competition switches the function of COP9 from self-renewal to differentiation.
abstract: The balance between stem cell self-renewal and differentiation is controlled by intrinsic factors and niche signals. In the Drosophila melanogaster ovary, some intrinsic factors promote germline stem cell (GSC) self-renewal, whereas others stimulate differentiation. However, it remains poorly understood how the balance between self-renewal and differentiation is controlled. Here we use D. melanogaster ovarian GSCs to demonstrate that the differentiation factor Bam controls the functional switch of the COP9 complex from self-renewal to differentiation via protein competition. The COP9 complex is composed of eight Csn subunits, Csn1-8, and removes Nedd8 modifications from target proteins. Genetic results indicated that the COP9 complex is required intrinsically for GSC self-renewal, whereas other Csn proteins, with the exception of Csn4, were also required for GSC progeny differentiation. Bam-mediated Csn4 sequestration from the COP9 complex via protein competition inactivated the self-renewing function of COP9 and allowed other Csn proteins to promote GSC differentiation. Therefore, this study reveals a protein-competition-based mechanism for controlling the balance between stem cell self-renewal and differentiation. Because numerous self-renewal factors are ubiquitously expressed throughout the stem cell lineage in various systems, protein competition may function as an important mechanism for controlling the self-renewal-to-differentiation switch.
authors.affiliation: 1] Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA [2] Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, 15 Da Tun Road, Beijing 100101, China [3].
authors.forename: Lei
authors.initials: L
authors.lastname: Pan
authors.affiliation: 1] Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA [2] Department of Cell Biology and Anatomy, University of Kansas School of Medicine, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA [3].
authors.forename: Su
authors.initials: S
authors.lastname: Wang
authors.affiliation: 1] Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China [2].
authors.forename: Tinglin
authors.initials: T
authors.lastname: Lu
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA.
authors.forename: Changjiang
authors.initials: C
authors.lastname: Weng
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Song
authors.affiliation: 1] Department of Molecular Biology and Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Park
authors.affiliation: Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Zhi-Hao
authors.initials: ZH
authors.lastname: Yang
authors.affiliation: 1] Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA [2] Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, 15 Da Tun Road, Beijing 100101, China.
authors.forename: Junjing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, 15 Da Tun Road, Beijing 100101, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Tang
authors.affiliation: 1] Department of Molecular Biology and Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: McKearin
authors.affiliation: Department of Plant Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Chamovitz
authors.affiliation: Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Jianquan
authors.initials: J
authors.lastname: Ni
authors.affiliation: 1] Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA [2] Department of Cell Biology and Anatomy, University of Kansas School of Medicine, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Xie
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001667:Binding, Competitive; D000075686:COP9 Signalosome Complex; D002454:Cell Differentiation; D049109:Cell Proliferation; D004265:DNA Helicases / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology* / Q000378:metabolism*; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism*; D000075687:NEDD8 Protein; D010053:Ovary / Q000166:cytology; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C520406:CSN4 protein, Drosophila; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D000075687:NEDD8 Protein; C513173:Nedd8 protein, Drosophila; D014452:Ubiquitins; C091674:bam protein, Drosophila; D010447:Peptide Hydrolases; C501491:CSN5 protein, Drosophila; D000075686:COP9 Signalosome Complex; D004265:DNA Helicases; C414082:bgcn protein, Drosophila