title: Autophagy mediates degradation of nuclear lamina.
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 diseases. 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 delivery, 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.
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Zhixun
authors.initials: Z
authors.lastname: Dou
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Caiyue
authors.initials: C
authors.lastname: Xu
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Donahue
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimi
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Ji-An
authors.initials: JA
authors.lastname: Pan
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Institute of Cancer Sciences, University of Glasgow and Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors.forename: Andrejs
authors.initials: A
authors.lastname: Ivanov
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Capell
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Drake
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Parisha P
authors.initials: PP
authors.lastname: Shah
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Catanzaro
authors.affiliation: Department of Biochemistry &Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: M Daniel
authors.initials: MD
authors.lastname: Ricketts
authors.affiliation: Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø - The Arctic University of Norway, 9037 Tromsø, Norway.
authors.forename: Trond
authors.initials: T
authors.lastname: Lamark
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Adam
authors.affiliation: Department of Biochemistry &Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Wei-Xing
authors.initials: WX
authors.lastname: Zong
authors.affiliation: Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø - The Arctic University of Norway, 9037 Tromsø, Norway.
authors.forename: Terje
authors.initials: T
authors.lastname: Johansen
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Goldman
authors.affiliation: Institute of Cancer Sciences, University of Glasgow and Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Adams
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D000071190:Autophagy-Related Protein 8 Family; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016922:Cellular Senescence; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005347:Fibroblasts; D057809:HEK293 Cells; D006801:Humans; D034921:Lamin Type B / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D034881:Nuclear Lamina / Q000378:metabolism*; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071190:Autophagy-Related Protein 8 Family; D002843:Chromatin; C498698:GABARAPL2 protein, human; D034921:Lamin Type B; C477012:MAP1LC3A protein, human; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D015689:Oncogene Protein p21(ras)