Autophagy-mediated degradation of nuclear envelope proteins during oncogene-induced senescence
Christelle Lenain1, Olga Gusyatiner2, Sirith Douma1
1Division of Molecular Oncology and.
Abstract:
Cellular senescence is a largely irreversible form of cell cycle arrest triggered by various types of damage and stress, including oncogene expression (termed oncogene-induced senescence or OIS). We and others have previously demonstrated that OIS occurs in human benign lesions, acting as a potent tumor suppressor mechanism. Numerous phenotypic changes occur during OIS, both in the cytoplasm and in the nucleus. These include the activation of autophagy, a catabolic process operating in the cytoplasm and downregulation of lamin B1, a component of the nuclear lamina. However, it is unknown whether these changes relate to each other. We discovered that cells entering BRAF(V600E)- or H-RAS(G12V)-induced senescence downregulate not only lamin B1 but also lamin A, as well as several other nuclear envelope (NE) proteins, resulting in an altered NE morphology. Depletion of LMNB1 or LMNA/C was sufficient to recapitulate some OIS features, including cell cycle exit and downregulation of NE proteins. We further found that the global loss of NE proteins is a consequence of their degradation by the autophagy machinery, which occurs concomitantly with autophagy induction and increased lysosomal content and activity. Our study therefore reveals a previously unknown connection between autophagy and the disruption of NE integrity during OIS.
Insights
Oncogene-induced senescence (OIS) involves nuclear envelope protein loss, linked to autophagy. This study reveals autophagy degrades nuclear envelope proteins, disrupting nuclear integrity during OIS.
Area of Science:
- Cellular and Molecular Biology
- Cancer Research
- Aging Biology
Background:
- Cellular senescence is an irreversible cell cycle arrest, crucial in tumor suppression.
- Oncogene-induced senescence (OIS) is a key mechanism preventing benign lesion progression.
- Phenotypic changes in OIS include cytoplasmic autophagy and nuclear lamin B1 downregulation.
Purpose of the Study:
- To investigate the relationship between autophagy and nuclear envelope changes during OIS.
- To determine if lamin downregulation is linked to autophagy-mediated degradation.
- To explore the role of nuclear envelope integrity in OIS.
Main Methods:
- Induction of senescence in human cells using oncogenes (BRAF(V600E), H-RAS(G12V)).
- Analysis of nuclear envelope protein levels (lamin B1, lamin A/C) and morphology.
- Assessment of autophagy markers, lysosomal activity, and protein degradation pathways.
- Genetic depletion of lamin B1 or lamin A/C to assess OIS features.
Main Results:
- OIS induction led to downregulation of lamin B1, lamin A, and other nuclear envelope proteins, altering nuclear morphology.
- Depletion of LMNB1 or LMNA/C mimicked some OIS characteristics, including cell cycle exit.
- Global loss of nuclear envelope proteins resulted from autophagic degradation, correlating with increased autophagy and lysosomal activity.
Conclusions:
- Autophagy is directly involved in the downregulation of nuclear envelope proteins during OIS.
- Disruption of nuclear envelope integrity via autophagy is a novel feature of OIS.
- This study uncovers a new link between autophagy and nuclear structure maintenance in senescence.
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