As a stress response, senescence is a dynamic process involving multiple effector mechanisms whose combination determines the phenotypic quality. Here we identify autophagy as a new effector mechanism of senescence. Autophagy is activated during senescence and its activation is correlated with negative feedback in the PI3K-mammalian target of rapamycin (mTOR) pathway. A subset of autophagy-related genes are up-regulated during senescence: Overexpression of one of those genes, ULK3, induces autophagy and senescence. Furthermore, inhibition of autophagy delays the senescence phenotype, including senescence-associated secretion. Our data suggest that autophagy, and its consequent protein turnover, mediate the acquisition of the senescence phenotype.Supplemental material is available at http://www.genesdev.org.Received December 24, 2008; revised version accepted February 11, 2009. Cellular senescence is a state of stable cell cycle arrest with active metabolism. Similar to apoptosis, senescence can be a failsafe program against a variety of cellular insults. In contrast to apoptosis, however, in which the cytotoxic signals converge to a common mechanism, senescence is typically a delayed stress response involving multiple effector mechanisms. These effector mechanisms include epigenetic regulation (Narita et al. 2006;Adams 2007), the DNA damage response (Bartkova et al. 2006;Di Micco et al. 2006;Mallette et al. 2007), and the senescence-associated secretion phenotype (Kortlever et al. 2006;Acosta et al. 2008;Coppé et al. 2008;Kuilman et al. 2008;Wajapeyee et al. 2008). The relative contribution of these effectors varies depending on the trigger and cell type.Oncogene-induced senescence (OIS) illustrates well the tumor-suppressive role of senescence (Collado and Serrano 2006). The initial phenotype of oncogene induction is a highly proliferative state, which mimics transformation. However, this mitotic burst is gradually replaced by senescence. Although it has been proposed that global and progressive epigenetic alterations play a crucial role in OIS (Narita et al. 2006), the precise mechanism by which cells can achieve such a dramatic change is still unclear.Autophagy is a genetically regulated program responsible for the turnover of cellular proteins and damaged or superfluous organelles. This evolutionarily conserved process is characterized by the formation of doublemembrane cytosolic vesicles, autophagosomes, which sequester cytoplasmic content and deliver it to lysosomes (Ohsumi 2001;Klionsky et al. 2007;Mizushima et al. 2008). Autophagy is often associated with acute metabolic changes and rapid protein replacement. For example, autophagy is required for preimplantation development, where maternal proteins are recycled by autophagy (Tsukamoto et al. 2008). Autophagy is also required for survival in the early neonatal starvation period (Kuma et al. 2004;Komatsu et al. 2005). In addition to these physiological conditions, cytotoxic stimuli can also activate autophagy, but its precise role as a stress response...
Autophagy, fundamentally a lysosomal degradation pathway, functions in cells during normal growth and certain pathological conditions, including starvation, to maintain homeostasis. Autophagosomes are formed through a mechanism that is not well understood, despite the identification of many genes required for autophagy. We have studied the mammalian homologue of Atg9p, a multi-spanning transmembrane protein essential in yeast for autophagy, to gain a better understanding of the function of this ubiquitious protein. We show that both the N-and C-termini of mammalian Atg9 (mAtg9) are cytosolic, and predict that mAtg9 spans the membrane six times. We find that mAtg9 is located in the trans-Golgi network and late endosomes and colocalizes with TGN46, the cation-independent mannose-6-phosphate receptor, Rab7 and Rab9. Amino acid starvation or rapamycin treatment, which upregulates autophagy, causes a redistribution of mAtg9 from the TGN to peripheral, endosomal membranes, which are positive for the autophagosomal marker GFP-LC3. siRNA-mediated depletion of the putative mammalian homologue of Atg1p, ULK1, inhibits this starvation-induced redistribution. The redistribution of mAtg9 also requires PI 3-kinase activity, and is reversed after restoration of amino acids. We speculate that starvation-induced autophagy, which requires mAtg9, may rely on an alteration of the steadystate trafficking of mAtg9, in a Atg1-dependent manner.Supplementary material available online at
Protein synthesis and autophagic degradation are regulated in an opposite manner by mammalian target of rapamycin (mTOR), whereas under certain conditions it would be beneficial if they occured in unison to handle rapid protein turnover. We observed a distinct cellular compartment at the trans-side of the Golgi apparatus, the ‘TOR-autophagy spatial coupling compartment’ (TASCC), where (auto)lysosomes and mTOR accumulated during Ras-induced senescence. mTOR recruitment to the TASCC was amino acid- and Rag guanosine triphosphatase (GTPase)-dependent, and disruption of mTOR localization to the TASCC suppressed interleukin-6/8 synthesis. TASCC-formation was observed during macrophage differentiation and in glomerular podocytes; both displayed increased protein secretion. The spatial coupling of cells’ catabolic and anabolic machinery could augment their respective functions and facilitate the mass synthesis of secretory proteins.
The core aspect of the senescent phenotype is a stable state of cell cycle arrest. However, this is a disguise that conceals a highly active metabolic cell state with diverse functionality. Both the cell-autonomous and the non-cell-autonomous activities of senescent cells create spatiotemporally dynamic and context-dependent tissue reactions. For example, the senescence-associated secretory phenotype (SASP) provokes not only tumour-suppressive but also tumour-promoting responses. Senescence is now increasingly considered to be an integrated and widespread component that is potentially important for tumour development, tumour suppression and the response to therapy.
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