Autophagy mediates degradation of nuclear lamina
Open accessAbstract
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.
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Lamin B1 loss and reduced nuclear integrity is suggested to fuel the SASP by contributing to CCF formation, stimulating the cGAS-STING pathway and interferon response.
“Furthermore, lamin B1 loss and reduced nuclear integrity is suggested to fuel the SASP by contributing to CCF formation (Dou et al., 2015; Ivanov et al., 2013), thereby stimulating the cGAS-STING pathway and interferon response (see Secretion) (Li and Chen, 2018).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Dou et al., 2015
In the passage labeled Abstract (page unavailable), Dou et al. report reduced lamin B1 at the nuclear lamina, nuclear membrane blebbing, and cytoplasmic chromatin fragments in senescent cells. They also report that blocking LC3–lamin B1 interaction delayed the appearance of those fragments. These findings support a link to CCF formation, but the paper does not establish that this process fuels the SASP; the citing sentence assigns the downstream cGAS–STING claim to a different citation. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCellular senescence is accompanied by substantial reorganization of the nuclear envelope and a breakdown in nucleocytoplasmic trafficking, including altered expression and degradation of Lamin B1, and formation of cytoplasmic chromatin fragments.
“Cellular senescence is accompanied by substantial reorganization of the nuclear envelope and a breakdown in nucleocytoplasmic trafficking, including altered expression and degradation of Lamin B1, and the formation of cytoplasmic chromatin fragments (CCFs) [38–45].”
From Chemically induced reprogramming to reverse cellular aging (2023) · cites this paper as [40]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredLoss of nuclear lamina can release cytosolic chromatin fragments into the cytoplasm of senescent cells.
“Loss of nuclear lamina can lead to the release of cytosolic chromatin fragments (CCFs) in the cytoplasm of senescent cells58–60”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [59]
Autophagy-mediated CCF formation together with reduced histone synthesis might lead to global loss of core histones during senescence, affecting the chromatin landscape.
“Autophagy-mediated CCF formation (Dou et al., 2015) together with reduced histone synthesis (O'Sullivan et al., 2010) might also lead to a global loss of core histones during senescence, affecting the chromatin landscape (Chan and Narita, 2019; Ivanov et al., 2013).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Dou et al., 2015
Downregulation of lamin B1 is a key feature of senescence.
“Downregulation of lamin B1, a major component of the nuclear lamina, is another key feature of senescence (Dou et al., 2015; Freund et al., 2012; Shah et al., 2013; Shimi et al., 2011).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Dou et al., 2015
CCF may serve as a vehicle for degradation of Lamin B1.
“suggesting that, at least in part, CCF are a vehicle for degradation of Lamin B1.”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Dou et al., 2015
CCF may function as a reservoir for nuclear autophagy substrates.
“The observation that Lamin B1 in CCF is degraded by autophagy (Dou et al., 2015) suggests that CCF may function as a reservoir for nuclear autophagy substrates.”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Dou et al., 2015
CCF can be found inside double-membrane autophagosomes in oncogene-induced senescent cells.
“Electron microscopy of oncogene-induced senescent cells show that CCF can localize within double membrane-enclosed autophagosomes”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Dou et al., 2015
Degradation by autophagy has been proposed for CCF and MN.
“Degradation by autophagy has also been proposed for CCF and MN (Dou et al., 2015; Rello-Varona et al., 2012; Sagona et al., 2014).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Dou et al., 2015
CCF are found together with lysosomes in a process requiring macroautophagy.
“fluorescence microscopy shows that CCF colocalize with lysosomes, dependent on activation of macroautophagy (Dou et al., 2015)”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Dou et al., 2015
The autophagosome can selectively degrade endoplasmic reticulum and nucleus, and this degradation can lead to loss of nuclear lamina.
“Intriguingly, it was recently discovered that the autophagosome can selectively degrade the endoplasmic reticulum and the nucleus (Mochida et al., 2015), and that this degradation can lead to a loss of the nuclear lamina (Dou et al., 2015).”
From The Aging Epigenome (2016) · cites this paper as Dou et al., 2015
Upon oncogene activation, lamin B1 and LC3 interact with lamina-associated domains and are extruded through nuclear blebbing into cytoplasm, forming CCFs that are degraded by cytoplasmic autophagy.
“Conversely, upon oncogene activation, lamin B1 and LC3 interact with lamina-associated domains (i.e., transcriptionally inactive heterochromatin) and are extruded through nuclear blebbing into the cytoplasm, forming CCFs that are then degraded by cytoplasmic autophagy.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [247]
OIS relies on autophagic turnover of cytoplasmic material and specific autophagic degradation of nuclear lamin B1 in lysosomes, delivered by nucleus-to-cytoplasm transport.
“OIS relies not only on the autophagic turnover of cytoplasmic material but also on the specific autophagic degradation of nuclear lamin B1 in lysosomes, where it is delivered by nucleus-to-cytoplasm transport [247].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [247]
Autophagy inhibition maintains nuclear envelope integrity in senescent cells by suppressing lamin B1 degradation and CCFs formation.
“Importantly, autophagy inhibition maintains the nuclear envelope integrity in senescent cells by suppressing lamin B1 degradation and CCFs formation [247].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [247]
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DNA Damage Response and Autophagy: A Meaningful Partnership
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Histone Acetyltransferase p300 Induces De Novo Super-Enhancers to Drive Cellular Senescence
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- Authors
- Dou, Z., Xu, C., Donahue, G., Shimi, T., Pan, J.-A., Zhu, J., Ivanov, A., Capell, B. C., Drake, A. M., Shah, P. P., Catanzaro, J. M., Daniel Ricketts, M., Lamark, T., Adam, S. A., Marmorstein, R., Zong, W.-X., Johansen, T., Goldman, R. D., Adams, P. D., & Berger, S. L.
- Affiliations
- University of Pennsylvania (US)
- Northwestern University (US)
- Stony Brook University (US)
- Cancer Research UK Scotland Institute (GB)
- UiT The Arctic University of Norway (NO)
- Abramson Cancer Center (US)
- Corresponding author
- Berger, Shelley L.
- ORCID
- Venue
- Nature
- Published
- 2015-10-28
- Volume
- 527
- Issue
- 7576
- Pages
- 105-109
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4824414
- OpenAlex
- W2159591471
- Cited by
- 655
- References
- 41
- Citations by year
- 2026: 38 · 2025: 56 · 2024: 58 · 2023: 55 · 2022: 63 · 2021: 88 · 2020: 80 · 2019: 68 · 2018: 57 · 2017: 44 · 2016: 45 · 2015: 3
- FWCI
- 38.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- Funders
- Cancer Research UK (22311)
- National Institute on Aging (P01AG031862)
- National Cancer Institute (R01CA129536, R01CA078831, P30CA060553)
- National Institute of General Medical Sciences (R01GM106023, R01GM097355)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR007465)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- autophagy, nuclear lamina, lamin B1, LC3, oncogenic Ras, oncogene-induced senescence, lysosomal degradation, chromatin, carcinogenesis
- MeSH terms
- Autophagy-Related Protein 8 Family, Animals, Autophagy, Cell Transformation, Neoplastic, Cells, Cultured, Chromatin, Cytoplasm, Fibroblasts, Humans, Lysosomes, Microfilament Proteins, Microtubule-Associated Proteins, Protein Binding, Oncogene Protein p21(ras), Cellular Senescence, Nuclear Lamina, Lamin Type B, Adaptor Proteins, Signal Transducing, Mice, HEK293 Cells, Proteolysis
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