Nucleolar expansion and elevated protein translation in premature aging

Nature Communications - Tập 8 Số 1
Abigail Buchwalter1, Martin W. Hetzer1
1Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, USA

Tóm tắt

AbstractPremature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging.

Từ khóa


Tài liệu tham khảo

Eriksson, M. et al. Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423, 293–298 (2003).

Gordon, L. B., Rothman, F. G., López-Otín, C. & Misteli, T. Progeria: a paradigm for translational medicine. Cell 156, 400–407 (2014).

Burke, B. & Stewart, C. L. The nuclear lamins: flexibility in function. Nat. Rev. Mol. Cell Biol. 14, 13–24 (2013).

Zullo, J. M. et al. DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina. Cell 149, 1474–1487 (2012).

Gesson, K. et al. A-type lamins bind both hetero- and euchromatin, the latter being regulated by lamina-associated polypeptide 2 alpha. Genome Res. 26, 462–473 (2016).

Beck, L. A., Hosick, T. J. & Sinensky, M. Isoprenylation is required for the processing of the lamin A precursor. J. Cell Biol. 110, 1489–1499 (1990).

Moulson, C. L. et al. Homozygous and compound heterozygous mutations in ZMPSTE24 cause the laminopathy restrictive dermopathy. J. Invest. Dermatol. 125, 913–919 (2005).

Mariño, G. et al. Premature aging in mice activates a systemic metabolic response involving autophagy induction. Hum. Mol. Genet. 17, 2196–2211 (2008).

Scaffidi, P. & Misteli, T. Lamin A–dependent nuclear defects in human aging. Science 312, 1059–1063 (2006).

Rodriguez, S., Coppedè, F., Sagelius, H. & Eriksson, M. Increased expression of the Hutchinson-Gilford progeria syndrome truncated lamin A transcript during cell aging. Eur. J. Hum. Genet. 17, 928–937 (2009).

McClintock, D. et al. The mutant form of lamin a that causes hutchinson-gilford progeria is a biomarker of cellular aging in human skin. PLoS ONE 2, e1269 (2007).

Goldman, R. D. et al. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc. Natl Acad. Sci. 101, 8963–8968 (2004).

Vidak, S., Kubben, N., Dechat, T. & Foisner, R. Proliferation of progeria cells is enhanced by lamina-associated polypeptide 2α (LAP2α) through expression of extracellular matrix proteins. Genes Dev. 29, 2022–2036 (2015).

Shumaker, D. K. & Goldman, R. D. Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc. Natl Acad. Sci. 103, 8703–8708 (2006).

Kubben, N., Brimacombe, K. R., Donegan, M., Li, Z. & Misteli, T. A high-content imaging-based screening pipeline for the systematic identification of anti-progeroid compounds. Methods 96, 46–58 (2016).

Kubben, N. et al. Repression of the Antioxidant NRF2 pathway in premature. Aging Cell 165, 1361–1374 (2016).

Liu, B. et al. Genomic instability in laminopathy-based premature aging. Nat. Med. 11, 780–785 (2005).

Viteri, G., Chung, Y. W. & Stadtman, E. R. Effect of progerin on the accumulation of oxidized proteins in fibroblasts from Hutchinson Gilford progeria patients. Mech. Ageing Dev. 131, 2–8 (2010).

Gabriel, D., Roedl, D., Gordon, L. B. & Djabali, K. Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts. Aging Cell 14, 78–91 (2015).

Rivera-Torres, J. et al. Identification of mitochondrial dysfunction in Hutchinson–Gilford progeria syndrome through use of stable isotope labeling with amino acids in cell culture. J. Proteomics 91, 466–477 (2013).

Scaffidi, P. & Misteli, T. Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing. Nat. Cell Biol. 10, 452–459 (2008).

Rossi, D. J., Jamieson, C. H. M. & Weissman, I. L. Stems cells and the pathways to aging and cancer. Cell 132, 681–696 (2008).

Cao, K. et al. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. Sci. Transl. Med. 3, 89ra58–89ra58 (2011).

Cenni, V. & Lattanzi, G. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria. Eur. J. Histochem. 55, e36 (2011).

Burke, B. & Stewart, C. L. Functional architecture of the cell's nucleus in development, aging, and disease. Curr. Top. Dev. Biol. 109, 1–52 (2014).

Ong, S.-E. & Mann, M. A practical recipe for stable isotope labeling by amino acids in cell culture (SILAC). Nat. Protoc. 1, 2650–2660 (2007).

Wu, R. S., Tsai, S. & Bonner, W. M. Patterns of histone variant synthesis can distinguish go from gl cells. Cell 31, 367–374 (1982).

Bridger, J. M. & Kill, I. R. Aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis. Exp. Gerontol. 39, 717–724 (2004).

Thoreen, C. C. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 486, 109–113 (2012).

Ramos, F. J. et al. Rapamycin reverses elevated mTORC1 signaling in lamin A/C–deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci. Transl. Med. 4, 144ra103–144ra103 (2012).

Liao, C.-Y. et al. Rapamycin reverses metabolic deficits in lamin A/C-deficient mice. Cell Rep. 17, 2542–2552 (2016).

Wandrey, F. et al. The NF45/NF90 heterodimer contributes to the biogenesis of 60S ribosomal subunits and influences nucleolar morphology. Mol. Cell Biol. 35, 3491–3503 (2015).

Thiry, M. & Lafontaine, D. L. J. Birth of a nucleolus: the evolution of nucleolar compartments. Trends Cell Biol. 15, 194–199 (2005).

McStay, B. & Grummt, I. The epigenetics of rRNA genes: from molecular to chromosome biology. Annu. Rev. Cell Dev. Biol. 24, 131–157 (2008).

McCord, R. P. et al. Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome. Genome Res. 23, 260–269 (2013).

Brown, S. E. & Szyf, M. Epigenetic programming of the rRNA promoter by MBD3. Mol. Cell Biol. 27, 4938–4952 (2007).

Badertscher, L. et al. Genome-wide RNAi screening identifies protein modules required for 40S subunit synthesis in human cells. Cell Rep. 13, 2879–2891 (2015).

Tafforeau, L. et al. The complexity of human ribosome biogenesis revealed by systematic nucleolar screening of Pre-rRNA processing factors. Mol. Cell 51, 539–551 (2013).

Bridger, J. M., Kill, I. R., O’Farrell, M. & Hutchison, C. J. Internal lamin structures within G1 nuclei of human dermal fibroblasts. J. Cell Sci. 104, 297–306 (1993).

Kennedy, B. K., Barbie, D. A., Classon, M., Dyson, N. & Harlow, E. Nuclear organization of DNA replication in primary mammalian cells. Genes Dev. 14, 2855–2868 (2000).

Gesson, K. et al. A-type lamins bind both hetero- and euchromatin, the latter being regulated by lamina-associated polypeptide 2 alpha. Genome Res. 26, 462–473 (2016).

Hansen, M. et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6, 95–110 (2007).

Pan, K. Z. et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell 6, 111–119 (2007).

Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).

Tiku, V. et al. Small nucleoli are a cellular hallmark of longevity. Nat. Commun. 8, 16083 (2017).

Bollati, V. et al. Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech. Ageing Dev. 130, 234–239 (2009).

Scaffidi, P. & Misteli, T. Lamin A-dependent nuclear defects in human aging. Science 312, 1059–1063 (2006).

Osorio, F. G. et al. Nuclear envelope alterations generate an aging-like epigenetic pattern in mice deficient in Zmpste24 metalloprotease. Aging Cell 9, 947–957 (2010).

Osorio, F. G. et al. Splicing-directed therapy in a new mouse model of human accelerated aging. Sci. Transl. Med. 3, 106ra107–106ra107 (2011).

Zeller, P. et al. Histone H3K9 methylation is dispensable for caenorhabditis elegans development but suppresses RNA:DNA hybrid-associated repeat instability. Nat. Genet. 48, 1385–1395 (2016).

Peng, J. C. & Karpen, G. H. H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability. Nat. Cell Biol. 9, 25–35 (2007).

Lempiäinen, H. & Shore, D. Growth control and ribosome biogenesis. Curr. Opin. Cell Biol. 21, 855–863 (2009).

MacInnes, A. The role of the ribosome in the regulation of longevity and lifespan extension. Wiley Interdiscip. Rev. RNA 7, 198–212 (2016).

Villee, D. B., Nichols, G. & Talbot, N. B. Metabolic studies in two boys with classical progeria. Pediatrics 43, 207–216 (1969).

Merideth, M. Phenotype and course of hutchinson–gilford progeria syndrome. New Eng. J. Med. 358, 592–604 (2008).

Abdenur, J., Brown, W. T., Friedman, S., Smith, M. & Lifshitz, F. Response to nutritional and growth hormone treatment in progeria. Metabolism 46, 851–856 (1997).

López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

Liu, L. & Rando, T. A. Manifestations and mechanisms of stem cell aging. J. Cell Biol. 193, 257–266 (2011).

Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013).

Kudlow, B. A., Stanfel, M. N., Burtner, C. R., Johnston, E. D. & Kennedy, B. K. Suppression of proliferative defects associated with processing-defective lamin A mutants by hTERT or inactivation of p53. Mol. Biol. Cell 19, 5238–5248 (2008).

Sinclair, D. A., Mills, K. & Guarente, L. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science 277, 1313–1316 (1997).

Sinclair, D. A. & Guarente, L. Extrachromosomal rDNA circles--a cause of aging in yeast. Cell 91, 1033–1042 (1997).

Vukoti, K. et al. Monitoring newly synthesized proteins over the adult life span of Caenorhabditis elegans. J. Proteome. Res. 14, 1483–1494 (2015).

Dhondt, I. et al. FOXO/DAF-16 activation slows down turnover of the majority of proteins in C. elegans. Cell Rep. 16, 3028–3040 (2016).

Kennedy, B. K. & Kaeberlein, M. Hot topics in aging research: protein translation, 2009. Aging Cell 8, 617–623 (2009).

Bywater, M. J. et al. Inhibition of RNA polymerase i as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell 22, 51–65 (2012).

Schirmer, E. C., Florens, L., Guan, T., Yates, J. R. & Gerace, L. Nuclear membrane proteins with potential disease links found by subtractive proteomics. Science 301, 1380–1382 (2003).

Ma, J. et al. Improved identification and analysis of small open reading frame encoded polypeptides. Anal. Chem. 88, 3967–3975 (2016).

He, L., Diedrich, J., Chu, Y.-Y. & Yates, J. R. Extracting accurate precursor information for tandem mass spectra by rawconverter. Anal. Chem. 87, 11361–11367 (2015).

Xu, T. et al. ProLuCID: an improved SEQUEST-like algorithm with enhanced sensitivity and specificity. J. Proteomics 129, 16–24 (2015).

Tabb, D. L., McDonald, W. H. & Yates, J. R. DTASelect and contrast: tools for assembling and comparing protein identifications from shotgun proteomics. J. Proteome Res. 1, 21–26 (2002).

Park, S. K. R. et al. Census 2: isobaric labeling data analysis. Bioinformatics 30, 2208–2209 (2014).

Bensaude, O. Inhibiting eukaryotic transcription: which compound to choose? How to evaluate its activity? Transcription 2, 103–108 (2011).