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Nuclear Export Inhibition Enhances HLH-30/TFEB Activity, Autophagy, and Lifespan

Silvestrini, Melissa J., Johnson, Joseph R., Kumar, Anita V., Thakurta, Tara G., Blais, Karine, Neill, Zachary A., Marion, Sarah W., St. Amand, Victoria, Reenan, Robert A., Lapierre, Louis R.·2018·Cell Reports
DOI 10.1016/j.celrep.2018.04.063PMC PMC5991088
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Figure 1 XPO-1 Modulates Nuclear Localization of HLH-30/TFEB and Autophagy (A) Nematodes expressing HLH-30::GFP were fed control bacteria or bacteria expressing RNAi against xpo-1 during development or during adulthood for 48 hr (1003 magnification). (B) Expression levels of xpo-1, lgg-1, lgg-2, sqst-1, and hlh-30 were measured by qPCR in animals fed control bacteria or bacteria expressing RNAi against xpo-1 from day 1 to day 5 of adulthood. *p < 0.05; **p < 0.01; n = 4. Error bars represent ± SD, t test. (C and D) Autophagosome (AP) and autolysosome (AL) formation was measured in hypodermal seam cells (C) and pharynx (D) of wild-type and hlh-30(tm1978) animals expressing tandem autophagy reporter mCherry::GFP::LGG-1 and fed control bacteria or bacteria expressing RNAi against xpo-1 for 48 hr during early adulthood. *p < 0.05; **p < 0.01; N = 8. Error bars represent ± SD, t test. (E) Effect of xpo-1 silencing during 7 days of adulthood on heat resistance was assayed. p < 0.05, n = 200, Mantel-Cox log rank. See Table S1 for statistical analyses and repeats. (F–H) Accumulation of Aβ42 (F) and Q35::YFP punctae (Gand H) were measured in transgenic animals fed control bacteria or bacteria expressing RNAi against xpo-1 during 5 days of adulthood; images are shown in (G), and quantification is given in (H). *p < 0.05. Q35::YFP, n = 5; Aβ42, n = 100. Error bars represent ± SD, t test.
Figure 1 XPO-1 Modulates Nuclear Localization of HLH-30/TFEB and Autophagy (A) Nematodes expressing HLH-30::GFP were fed control bacteria or bacteria expressing RNAi against xpo-1 during development or during adulthood for 48 hr (1003 magnification). (B) Expression levels of xpo-1, lgg-1, lgg-2, sqst-1, and hlh-30 were measured by qPCR in animals fed control bacteria or bacteria expressing RNAi against xpo-1 from day 1 to day 5 of adulthood. *p < 0.05; **p < 0.01; n = 4. Error bars represent ± SD, t test. (C and D) Autophagosome (AP) and autolysosome (AL) formation was measured in hypodermal seam cells (C) and pharynx (D) of wild-type and hlh-30(tm1978) animals expressing tandem autophagy reporter mCherry::GFP::LGG-1 and fed control bacteria or bacteria expressing RNAi against xpo-1 for 48 hr during early adulthood. *p < 0.05; **p < 0.01; N = 8. Error bars represent ± SD, t test. (E) Effect of xpo-1 silencing during 7 days of adulthood on heat resistance was assayed. p < 0.05, n = 200, Mantel-Cox log rank. See Table S1 for statistical analyses and repeats. (F–H) Accumulation of Aβ42 (F) and Q35::YFP punctae (Gand H) were measured in transgenic animals fed control bacteria or bacteria expressing RNAi against xpo-1 during 5 days of adulthood; images are shown in (G), and quantification is given in (H). *p < 0.05. Q35::YFP, n = 5; Aβ42, n = 100. Error bars represent ± SD, t test.CC BY · PubMed Central
Figure 2 Silencing xpo-1 Extends Lifespan in C. elegans (A–I) Lifespan analyses of (A) wild-type (WT), (B) hlh-30(tm1978), (C) daf-16(mu86), (D) atg-7(bp411), (E) atg-18(gk378), (F) daf-36(k114), (G) glp-1(e2144), (H) eat-2(ad1116), and (I) rsks-1(sv31) fed control bacteria or bacteria expressing RNAi against xpo-1 from day 1 of adulthood. n = 100, Mantel-Cox log rank. See also Table S1 for statistical analyses and repeats.
Figure 2 Silencing xpo-1 Extends Lifespan in C. elegans (A–I) Lifespan analyses of (A) wild-type (WT), (B) hlh-30(tm1978), (C) daf-16(mu86), (D) atg-7(bp411), (E) atg-18(gk378), (F) daf-36(k114), (G) glp-1(e2144), (H) eat-2(ad1116), and (I) rsks-1(sv31) fed control bacteria or bacteria expressing RNAi against xpo-1 from day 1 of adulthood. n = 100, Mantel-Cox log rank. See also Table S1 for statistical analyses and repeats.CC BY · PubMed Central
Figure 3 Pharmacological Inhibition of XPO-1/Embargoed Promotes Autophagy and Longevity (A) Day 1 animals expressing HLH-30::GFP were fed E. coli OP50 bacteria with DMSO (0.1%) or KPT-330 (25, 50, or 100 µM). 100× magnification. (B) Lifespan analysis of wild-type animals fed bacteria with DMSO (0.1%) or KPT-330 (25, 50, or 100 µM). (C and D) Autophagosome (AP) and autolysosome (AL) were quantified in the pharynx (C) and in hypodermal seam cells (D) of animals expressing mCherry::GFP::LGG-1 and fed bacteria with DMSO (0.1%) or KPT-330 (50 or 100 µM) from day 1 to day 3 of adulthood. **p < 0.01; n = ~10. Error bars represent ± SD, t test. (E) Heat stress assay of animals fed bacteria with DMSO (0.1%) or KPT-330 (100 µM) from day 1 to day 5 of adulthood. p < 0.05; n~100. (F) Lifespan analysis of the ALS model in flies (dsodH71Y) fed food with DMSO (0.1%) or KPT-330 (100 µM). p < 0.05; n > 300, Mantel-Cox log rank. See Table S2 for statistical analyses and repeats.
Figure 3 Pharmacological Inhibition of XPO-1/Embargoed Promotes Autophagy and Longevity (A) Day 1 animals expressing HLH-30::GFP were fed E. coli OP50 bacteria with DMSO (0.1%) or KPT-330 (25, 50, or 100 µM). 100× magnification. (B) Lifespan analysis of wild-type animals fed bacteria with DMSO (0.1%) or KPT-330 (25, 50, or 100 µM). (C and D) Autophagosome (AP) and autolysosome (AL) were quantified in the pharynx (C) and in hypodermal seam cells (D) of animals expressing mCherry::GFP::LGG-1 and fed bacteria with DMSO (0.1%) or KPT-330 (50 or 100 µM) from day 1 to day 3 of adulthood. **p < 0.01; n = ~10. Error bars represent ± SD, t test. (E) Heat stress assay of animals fed bacteria with DMSO (0.1%) or KPT-330 (100 µM) from day 1 to day 5 of adulthood. p < 0.05; n~100. (F) Lifespan analysis of the ALS model in flies (dsodH71Y) fed food with DMSO (0.1%) or KPT-330 (100 µM). p < 0.05; n > 300, Mantel-Cox log rank. See Table S2 for statistical analyses and repeats.CC BY · PubMed Central
Figure 4 Nuclear Enrichment of TFEB and Autophagy Are Stimulated by XPO1 Inhibition (A) TFEB-GFP-expressing HeLa cells were imaged after incubation for 6 hr in a medium containing vehicle or compounds (Torin 1, 5 µM; KPTs, 1 µM). Scale bars, 20 µm. (B) Percentage of cells with TFEB nuclear localization was quantified from four independent experiments. ***p < 0.001. Error bars represent ± SD, t test. (C and D) HeLa cells were grown in medium containing vehicle or compounds for 6 hr, lysosomes were visualized with Lysotracker Red (C), and signal intensities were quantified (D). **p < 0.01; ***p < 0.001. Scale bars, 50 µm. #Image taken at half the exposure for representational purposes. (E) HeLa cells were grown in a medium containing vehicle or compounds for 24 hr, and proteins were visualized by immunoblotting. (F) Levels of LC3 I and II were quantified by densitometry. *p < 0.05; **p < 0.01; ***p < 0.001. Error bars represent ± SD, one-way ANOVA. Images and blots are representative of three independent experiments.
Figure 4 Nuclear Enrichment of TFEB and Autophagy Are Stimulated by XPO1 Inhibition (A) TFEB-GFP-expressing HeLa cells were imaged after incubation for 6 hr in a medium containing vehicle or compounds (Torin 1, 5 µM; KPTs, 1 µM). Scale bars, 20 µm. (B) Percentage of cells with TFEB nuclear localization was quantified from four independent experiments. ***p < 0.001. Error bars represent ± SD, t test. (C and D) HeLa cells were grown in medium containing vehicle or compounds for 6 hr, lysosomes were visualized with Lysotracker Red (C), and signal intensities were quantified (D). **p < 0.01; ***p < 0.001. Scale bars, 50 µm. #Image taken at half the exposure for representational purposes. (E) HeLa cells were grown in a medium containing vehicle or compounds for 24 hr, and proteins were visualized by immunoblotting. (F) Levels of LC3 I and II were quantified by densitometry. *p < 0.05; **p < 0.01; ***p < 0.001. Error bars represent ± SD, one-way ANOVA. Images and blots are representative of three independent experiments.CC BY · PubMed Central

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Metadata

Authors
Silvestrini, M. J., Johnson, J. R., Kumar, A. V., Thakurta, T. G., Blais, K., Neill, Z. A., Marion, S. W., St. Amand, V., Reenan, R. A., & Lapierre, L. R.
Venue
Cell Reports
Publisher
Elsevier BV
Published
2018-05
Volume
23
Issue
7
Pages
1915-1921
ISSN
2211-1247
DOI
10.1016/j.celrep.2018.04.063
PMC
PMC5991088
Cited by
101
References
3
Language
en
Licence
Funders
  • American Federation for Aging Research
  • Glenn Foundation for Medical Research

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Silvestrini, M. J., Johnson, J. R., Kumar, A. V., Thakurta, T. G., Blais, K., Neill, Z. A., Marion, S. W., St. Amand, V., Reenan, R. A., & Lapierre, L. R. (2018). Nuclear Export Inhibition Enhances HLH-30/TFEB Activity, Autophagy, and Lifespan. Cell Reports. https://doi.org/10.1016/j.celrep.2018.04.063