Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation

Rong, Yueguang; McPhee, Christina; Deng, Shuangshen; Huang, Lei; Chen, Lilian; Liu, Mei; Tracy, Kirsten M.; Baehrecke, Eric H.; Yu, Li; Lenardo, Michael J.

doi:10.1073/pnas.1013800108

Cited by 253 publications

(239 citation statements)

References 15 publications

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“…[7][8][9] Mutations in the corresponding genes results in aberrant autolysosome formation, leading to embryonic senescence and premature aging symptoms in Drosophila and zebrafish. 4,10 We recently have shown in zebrafish that Becn1/Beclin 1 suppression ameliorates developmental senescence and autolysosomal impairment associated with Spns1 deficiency, whereas loss of Tp53 exacerbates these characteristics in the Spns1-defective zebrafish embryos.…”

Section: Introductionmentioning

confidence: 99%

Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase

et al. 2016

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Spns1 (Spinster homolog 1 [Drosophila]) in vertebrates, as well as Spin (Spinster) in Drosophila, is a hypothetical lysosomal H C -carbohydrate transporter, which functions at a late stage of macroautophagy (hereafter autophagy). The Spin/Spns1 defect induces aberrant autolysosome formation that leads to developmental senescence in the embryonic stage and premature aging symptoms in adulthood. However, the molecular mechanism by which loss of Spin/Spns1 leads to the specific pathogenesis remains to be elucidated. Using chemical, genetic and CRISPR/Cas9-mediated genome-editing approaches in zebrafish, we investigated and determined a mechanism that suppresses embryonic senescence as well as autolysosomal impairment mediated by Spns1 deficiency. Unexpectedly, we found that a concurrent disruption of the vacuolar-type H C -ATPase (v-ATPase) subunit gene, atp6v0ca (ATPase, H C transporting, lysosomal, V0 subunit ca) led to suppression of the senescence induced by the Spns1 defect, whereas the sole loss of Atp6v0ca led to senescent embryos similar to the single spns1 mutation. Moreover, we discovered that the combined stable defect seen in the presence of both the spns1 and atp6v0ca mutant genes still subsequently induced premature autophagosome-lysosome fusion marked by insufficient acidity, while extending developmental life span, compared with the solely mutated spns1 defect. Our data suggest that Spns1 and the v-ATPase orchestrate proper autolysosomal biogenesis with optimal acidification that is critically linked to developmental senescence and survival.

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Section: Introductionmentioning

confidence: 99%

Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase

et al. 2016

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“…In Drosophila spinster mutants, lysosomes were larger than those in wild type fl ies (Dermaut et al, 2005). In mammalian cells, defects in Spinster lead to an accumulation of enlarged LAMP1-positive structures (Rong et al, 2011). Spinster was also found to take part in autophagic lysosome reformation (Rong et al, 2011).…”

Section: Screen Of 11 Candidates Associated With Fat Content In C Elmentioning

confidence: 99%

“…In mammalian cells, defects in Spinster lead to an accumulation of enlarged LAMP1-positive structures (Rong et al, 2011). Spinster was also found to take part in autophagic lysosome reformation (Rong et al, 2011). The localization and function of C13C4.5 have not yet been described in C. elegans.…”

Section: Screen Of 11 Candidates Associated With Fat Content In C Elmentioning

confidence: 99%

C13C4.5/Spinster, an evolutionarily conserved protein that regulates fertility in C. elegans through a lysosome-mediated lipid metabolism process

et al. 2013

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Lipid droplets, which are conserved across almost all species, are cytoplasmic organelles used to store neutral lipids. Identifi cation of lipid droplet regulators will be conducive to resolving obesity and other fat-associated diseases. In this paper, we selected 11 candidates that might be associated with lipid metabolism in Caenorhabditis elegans. Using a BODIPY 493/503-based fl ow cytometry screen, 6 negative and 3 positive regulators of fat content were identifi ed. We selected one negative regulator of lipid content, C13C4.5, for future study. C13C4.5 was mainly expressed in the worm intestine. We found that this gene was important for maintaining the metabolism of lipid droplets. Biochemical results revealed that 50% of triacylglycerol (TAG) was lost in C13C4.5 knockout worms. Stimulated Raman scattering (SRS) signals in C13C4.5 mutants showed only 49.6% of the fat content in the proximal intestinal region and 86.3% in the distal intestinal region compared with wild type animals. The mean values of lipid droplet size and intensity in C13C4.5 knockout animals were found to be signifi cantly decreased compared with those in wild type worms. The LMP-1-labeled membrane structures in worm intestines were also enlarged in C13C4.5 mutant animals. Finally, fertility defects were found in C13C4.5(ok2087) mutants. Taken together, these results indicate that C13C4.5 may regulate the fertility of C. elegans by changing the size and fat content of lipid droplets by interfering with lysosomal morphology and function.

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“…Therefore, this decrease in Akt activity reduces FoxO repression and permits the upregulation of protein, such as LC3, BNIP3 and ULK (4). In this manner, RAS-v12 overexpression induces an increase in autophagy that is associated with oncogene-induced senescence (OIS) hallmarks and also with the formation of TOR-autophagy spatial coupling compartment (TASCC) that mediates the secretion of interleukin-6/8, which are involved in senescence (5,6). If once transformation is established and the stress situation is maintained, this generates autophagy dependence or an increase in the glucose uptake as previously demonstrated (7,8).…”

Section: Introductionmentioning

confidence: 99%

Oncogene-mediated tumor transformation sensitizes cells to autophagy induction

2016

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Abstract. The process of tumorigenesis induces alterations in numerous cellular pathways including the main eukaryotic metabolic routes. It has been recently demonstrated that autophagy is part of the oncogene-induced senescence phenotype although its role in tumor establishment has not been completely clarified. In the present study, we showed that non-transformed cells are sensitized to mitochondrial stress and autophagy induction when they are transformed by oncogenes such as c-Myc or Ras. We observed that overexpression of c-Myc or Ras increased AMP-activated protein kinase (AMPK) phosphorylation and the expression of p62, a known partner for degradation by autophagy. The activation of AMPK was found to favor the activation of FoxO3 which was prevented by the inhibition of AMPK. The transcriptional activation mediated by FoxO3 upregulated genes such as BNIP3 and LC3. Finally, the transformation by oncogenes such as c-Myc and Ras predisposes tumor cells to autophagy induction as a consequence of mitochondrial stress and impairs tumor growth in vitro and in vivo, which may have therapeutic implications.

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Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation

Cited by 253 publications

References 15 publications

Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase

Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase

C13C4.5/Spinster, an evolutionarily conserved protein that regulates fertility in C. elegans through a lysosome-mediated lipid metabolism process

Oncogene-mediated tumor transformation sensitizes cells to autophagy induction

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