Selective autophagy degrades lamin B1 in response to oncogenic and genotoxic insults.
Major finding: Selective autophagy degrades lamin B1 in response to oncogenic and genotoxic insults.
Mechanism: Lamin B1 interacts with LC3 and translocates to lysosomes in response to oncogene activation.
Impact: Autophagy-mediated lamin B1 degradation drives senescence and may suppress tumorigenesis.
Autophagy promotes the degradation of cytoplasmic cellular components in response to various stimuli such as starvation, and is upregulated in response to oncogene-induced senescence. Although autophagy proteins also localize to the nucleus, it remains unclear whether autophagy mediates degradation of nuclear proteins. Dou and colleagues found that the autophagy protein LC3 (also known as ATG8) directly interacts with the nuclear lamina protein lamin B1, but not other lamins. This interaction occurred at the nuclear lamina and was dependent on lipidation of LC3. Furthermore, chromatin immunoprecipitation sequencing revealed genome-wide association of LC3 with transcriptionally inactive heterochromatin domains that have been shown to be associated with lamin B1. Lamin B1 protein levels were not affected by starvation but were selectively downregulated in primary cells in response to oncogenic HRASV12 expression, consistent with previous studies and suggesting that oncogene activation promotes autophagy-mediated degradation of lamin B1. In support of this idea, expression of HRASV12 triggered nuclear membrane blebbing, nucleus-to-cytoplasm transport of lamin B1, and localization of lamin B1 within autophagosomes and autolysosomes. Inhibition of autophagy via ATG7 knockdown impaired lamin B1 degradation in HRASV12-expressing cells, as well as in cells exposed to oxidative stress or undergoing DNA damage–induced senescence, and delayed oncogenic HRAS–induced senescence. Similarly, disruption of the LC3–lamin B1 interaction via overexpression of a lamin B1–derived peptide sufficient to interact with LC3 or mutation of lamin B1 residues essential for binding to LC3 diminished the nucleus-to-cytoplasm transport and degradation of lamin B1, attenuated both HRASV12-driven and replicative senescence, and enhanced colony formation. These findings identify lamin B1 as a selective autophagy substrate that is degraded in response to oncogenic or genotoxic insults to drive senescence. In addition, these data define a role for mammalian autophagy in regulating nuclear proteins and suggest that autophagy-mediated degradation of the nuclear lamina may suppress tumorigenesis.