Autophagy-mediated degradation of nuclear envelope proteins during oncogene-induced senescence

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.

Nuclear autophagy: An evolutionarily conserved mechanism of nuclear degradation in the cytoplasm

“…Multiple studies show a close association between the nuclear and sequestering membrane. 26,27,32,46,47 Together, these data indicate that the nuclear membrane may contribute to the autophagosomal membrane in addition to being an autophagic target. Future studies will characterize the molecular features of the nuclear autophagosomal membrane and the underlying molecular mechanisms that drive autophagic targeting of the nuclear membrane.…”

“…28 Recent studies have highlighted the importance of nuclear autophagy in physiological and pathological processes such as cancer. [29][30][31][32][33][34] Nevertheless, the underlying molecular mechanisms remain to be explored.…”

The impact of autophagy on the development of senescence in primary tubular epithelial cells

“…These findings are consistent with other reports showing that autophagy can trigger pro-senescent events when activated in response to cellular stress. 15,19,21,29 Constitutive baseline autophagy, on the other hand, seems to act usually in a senescence preventing manner playing a crucial role in healthy aging and life span extension. 23,30 In our previous work we have shown a rapid development of senescence in PTEC not only after g-irradiation but also under baseline conditions.…”

“…14 Based on the finding that stress-induced autophagy is often followed by the occurrence of senescent cells it was concluded that autophagy might act as a pro-senescent trigger. [15][16][17][18][19] Along these lines, Young et al first proposed autophagy as an effector mechanism for establishment of oncogenic senescence. 17 Autophagy was later also found to contribute to senescence of bile duct epithelial cells and progression toward primary biliary cirrhosis.…”

The Chromatin Landscape of Cellular Senescence

“…Another chromatin component, the linker histone H1, is also depleted in senescent cells [39]. In addition to histone depletion, a recent line of evidence points to a role for autophagy , a protein recycling mechanism, in the degradation of chromatin fragments in the cytoplasm in both RS and OIS [40], and of proteins associated with the nuclear lamina in OIS, including LMNB1 and LMNA [41, 42]. However, it is not completely clear whether H1 depletion is a consequence of the ejection of chromatin into the cytoplasm also known as cytoplasmic chromatin fragments), a decrease in histone synthesis, or other mechanisms [40, 43, 44].…”