Abstract

Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with human diseases1,2,3. Although extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known about the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery4,5,6, is present in the nucleus and directly interacts with the nuclear lamina protein lamin B1, and binds to lamin-associated domains on chromatin. This LC3–lamin B1 interaction does not downregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated RAS. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers lamin B1 to the lysosome. Inhibiting autophagy or the LC3–lamin B1 interaction prevents activated RAS-induced lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests that this new function of autophagy acts as a guarding mechanism protecting cells from tumorigenesis.

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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

LC3 and lamin B1 ChIP-seq data have been deposited in the NCBI Gene Expression Omnibus (GEO) database under accession number GSE63440.

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Acknowledgements

We thank members of the Berger, Adams, and Goldman laboratories for technical assistance and discussions. We acknowledge A. L. Stout for help with confocal microscopy, and the electron microscopy resource laboratory for assistance on TEM. We thank Z. Yue for sharing the GFP antibody and reading the manuscript, and M. Narita and R. Salama for help with LADs definition. Z.D. is supported by a fellow award from the Leukemia & Lymphoma Society. B.C.C. is supported by career development awards from the Dermatology Foundation, Melanoma Research Foundation, and American Skin Association. S.L.B., P.D.A. and R.M. are supported by NIA P01 grant (P01AG031862). S.L.B. is also supported by NIH R01 CA078831. R.D.G. is supported by R01 GM106023 and the Progeria Research Foundation.

Author information

Author notes

    • Andrejs Ivanov

    Present address: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

Affiliations

  1. Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Zhixun Dou
    • , Caiyue Xu
    • , Greg Donahue
    • , Jiajun Zhu
    • , Brian C. Capell
    • , Adam M. Drake
    • , Parisha P. Shah
    •  & Shelley L. Berger
  2. Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA

    • Takeshi Shimi
    • , Stephen A. Adam
    •  & Robert D. Goldman
  3. Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA

    • Ji-An Pan
    • , Joseph M. Catanzaro
    •  & Wei-Xing Zong
  4. Institute of Cancer Sciences, University of Glasgow and Beatson Institute for Cancer Research, Glasgow G61 1BD, UK

    • Andrejs Ivanov
    •  & Peter D. Adams
  5. Department of Biochemistry & Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • M. Daniel Ricketts
    •  & Ronen Marmorstein
  6. Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø – The Arctic University of Norway, 9037 Tromsø, Norway

    • Trond Lamark
    •  & Terje Johansen
  7. Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Ronen Marmorstein
  8. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Ronen Marmorstein

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Contributions

Z.D., A.I., P.D.A., and S.L.B. conceived the project. Z.D. performed most of the experiments. C.X., G.D., B.C.C., A.M.D., and P.P.S. performed and analysed ChIP-seq. T.S. performed three-dimensional structural illumination microscopy imaging. T.S., S.A.A., and R.D.G. contributed novel lamin reagents and experimental design. J.-A.P., J.M.C., and W.-X.Z. contributed novel autophagy and senescence reagents. J.Z. performed Atg7 knockdown. M.D.R. and R.M. contributed to the biochemistry characterization of LC3–lamin B1 interaction. T.L. and T.J. contributed novel autophagy constructs and experimental design. Z.D., P.D.A., and S.L.B. composed the manuscript. All authors reviewed the manuscript and discussed the work.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Shelley L. Berger.

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    Supplementary Information

    This file contains original western blot images for Figures 1-5.

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DOI

https://doi.org/10.1038/nature15548

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