Inhibition of the 60S ribosome biogenesis GTPase LSG1 causes endoplasmic reticular disruption and cellular senescence

Abstract

Cellular senescence is triggered by diverse stimuli and is characterized by long‐term growth arrest and secretion of cytokines and chemokines (termed the SASP—senescence‐associated secretory phenotype). Senescence can be organismally beneficial as it can prevent the propagation of damaged or mutated clones and stimulate their clearance by immune cells. However, it has recently become clear that senescence also contributes to the pathophysiology of aging through the accumulation of damaged cells within tissues. Here, we describe that inhibition of the reaction catalysed by LSG1, a GTPase involved in the biogenesis of the 60S ribosomal subunit, leads to a robust induction of cellular senescence. Perhaps surprisingly, this was not due to ribosome depletion or translational insufficiency, but rather through perturbation of endoplasmic reticulum homeostasis and a dramatic upregulation of the cholesterol biosynthesis pathway. The underlying transcriptomic signature is shared with several other forms of senescence, and the cholesterol biosynthesis genes contribute to the cell cycle arrest in oncogene‐induced senescence. Furthermore, targeting of LSG1 resulted in amplification of the cholesterol/ER signature and restoration of a robust cellular senescence response in transformed cells, suggesting potential therapeutic uses of LSG1 inhibition.

ATF3 drives senescence by reconstructing accessible chromatin profiles

“…Among them, FOXA1, PLAT, CD44, FGF5, DIO2 and other genes are upregulated, whereas PLCB1, SETBP1, EHD3, ZNF423, PHGDH and other genes are downregulated in multiple senescence systems(Chan et al, 2019; Cho et al, 2019; Galanos et al, 2016; Hari et al, 2019; Hernandez-Segura et al, 2017; Komseli et al, 2018; Lau, Porciuncula, Yu, Iwakura, & David, 2019; Leveque et al, 2019; Q. Li et al, 2013; Limbad et al, 2020; Lowe & Raj, 2014; Nagano et al, 2016; Pan et al, 2019; Pantazi et al, 2019; Suwan et al, 2009; Wu, Pepowski, Takahashi, & Kron, 2019; Zhou et al, 2010), as are consistent with our results. These genes are located in or near the regions of IARs or DARs respectively.…”

Functional heterogeneity in senescence

“…In terms of SASP compositions, ectopic overexpression of Notch Receptor 1 (NOTCH1) in IMR90s led to a highly specific primary senescence-dependent secretome, composed of collagens and TGF-β and a suppression of the RASV12G-driven secretome, normally consisting of IL6/8, CCL2/3 and MMP1/3 [38] ( Figure 1C). Moreover, impaired ribosomal biogenesis induced senescence leads to a similarly restricted but yet distinct SASP, characterised by TGF-β [16].…”

“…Besides proliferation-related telomere erosion and oncogenic insults, senescence is triggered by various intrinsic and extrinsic factors, such as DNA damage [ 12 ], accumulation of reactive oxygen species (ROS) [ 13 ], mitogen exposure [ 14 ], hypoxia [ 15 ], impaired ribosomal biogenesis [ 16 ] and mitochondrial dysfunction [ 17 ]. Post insult, cells exit the cell cycle by activation of TP53-mediated cyclin-dependent kinase inhibitor 1A (CDKN1A or p21) and/or RB1-mediated negative cell-cycle regulation via p15(INK4B) and p16(INK4A), with the involvement of DNA damage response (DDR) pathways [ 12 ].…”

Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence

“…Our results describe a new mechanism of senescence induction by cytoplasmic microbial sensing, adding to the essential triggers such as the DNA Damage Response, telomere attrition, oncogenic activation, mitochondrial damage or ribosome biogenesis inactivation (Gorgoulis et al, 2019;Pantazi et al, 2019). We also show that both the expression and the assembly of the caspase-4 non-canonical inflammasome are triggered upon oncogene activation.…”