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Protein competition switches the function of COP9 from self-renewal to differentiation

Nature volume 514, pages 233236 (09 October 2014) | Download Citation

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Abstract

The balance between stem cell self-renewal and differentiation is controlled by intrinsic factors and niche signals1,2. In the Drosophila melanogaster ovary, some intrinsic factors promote germline stem cell (GSC) self-renewal, whereas others stimulate differentiation3. 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 proteins4,5. 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.

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Acknowledgements

We thank Y. Yamashita, the Developmental Studies Hybridoma Bank and the Bloomington Drosophila Stock Center for reagents, Xie laboratory members for discussions, and D. Chao and R. Krumlauf for critical comments on the manuscript. This work was supported by the Stowers Institute for Medical Research (T.X.), the National Institutes of Health (GM64428, T.X.), the National Natural Science Foundation of China (31370909, L.P.) and the Ministry of Science and Technology of China (2012CB518900, L.P.).

Author information

Author notes

    • Lei Pan
    • , Su Wang
    •  & Tinglin Lu

    These authors contributed equally to this work.

Affiliations

  1. Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA

    • Lei Pan
    • , Su Wang
    • , Changjiang Weng
    • , Xiaoqing Song
    • , Junjing Yu
    •  & Ting Xie
  2. Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, 15 Da Tun Road, Beijing 100101, China

    • Lei Pan
    • , Junjing Yu
    •  & Hong Tang
  3. Department of Cell Biology and Anatomy, University of Kansas School of Medicine, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA

    • Su Wang
    •  & Ting Xie
  4. Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China

    • Tinglin Lu
    • , Jin Sun
    • , Zhi-Hao Yang
    •  & Jianquan Ni
  5. Department of Molecular Biology and Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA

    • Joseph K. Park
    •  & Dennis M. McKearin
  6. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA

    • Joseph K. Park
    •  & Dennis M. McKearin
  7. Department of Plant Sciences, Tel Aviv University, Tel Aviv 69978, Israel

    • Daniel A. Chamovitz

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Contributions

L.P., S.W., T.L. and T.X. conceived the project. L.P., S.W., T.L., C.W., X.S., J.K.P., J.Y., H.T., D.M.M. and T.X. collected and analysed the data. J.S., Z.-H.Y., D.A.C. and J.N. contributed the reagents. L.P., S.W., T.L. and T.X. prepared the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ting Xie.

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DOI

https://doi.org/10.1038/nature13562

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