Asymmetrically inherited multidrug resistance transporters are recessive determinants in cellular replicative ageing

Eldakak, Amr; Rancati, Giulia; Rubinstein, Boris; Paul, Parama; Conaway, Veronica; Li, Rong

doi:10.1038/ncb2085

Cited by 43 publications

(57 citation statements)

References 30 publications

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“…Protein aggregates, carbonylated proteins, and reactive oxygen species have also been reported to distribute asymmetrically between old mothers and their daughters (17)(18)(19)(20)(21)(22). Preferential retention of membrane transporters in the mother cells has also been associated with lifespan asymmetry (23,24). These observations support the general notion that mother cells retain aging factors to themselves, enabling their daughters to rejuvenate.…”

supporting

confidence: 75%

Systematic analysis of asymmetric partitioning of yeast proteome between mother and daughter cells reveals “aging factors” and mechanism of lifespan asymmetry

Yang

McCormick

Zheng

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Budding yeast divides asymmetrically, giving rise to a mother cell that progressively ages and a daughter cell with full lifespan. It is generally assumed that mother cells retain damaged, lifespan limiting materials ("aging factors") through asymmetric division. However, the identity of these aging factors and the mechanisms through which they limit lifespan remain poorly understood. Using a flow cytometry-based, high-throughput approach, we quantified the asymmetric partitioning of the yeast proteome between mother and daughter cells during cell division, discovering 74 mother-enriched and 60 daughterenriched proteins. While daughter-enriched proteins are biased toward those needed for bud construction and genome maintenance, mother-enriched proteins are biased towards those localized in the plasma membrane and vacuole. Deletion of 23 of the 74 motherenriched proteins leads to lifespan extension, a fraction that is about six times that of the genes picked randomly from the genome. Among these lifespan-extending genes, three are involved in endosomal sorting/endosome to vacuole transport, and three are nitrogen source transporters. Tracking the dynamic expression of specific mother-enriched proteins revealed that their concentration steadily increases in the mother cells as they age, but is kept relatively low in the daughter cells via asymmetric distribution. Our results suggest that some mother-enriched proteins may increase to a concentration that becomes deleterious and lifespan-limiting in aged cells, possibly by upsetting homeostasis or leading to aberrant signaling. Our study provides a comprehensive resource for analyzing asymmetric cell division and aging in yeast, which should also be valuable for understanding similar phenomena in other organisms.aging | asymmetric cell division | proteome C ellular aging and asymmetric cell division are intimately linked. In budding yeast, asymmetric cell division yields a mother cell and a daughter cell that are easily distinguishable under the microscope. Tracking the fate of the mother lineage led to the discovery that individual mother cells have a finite replicative lifespan, defined by the number of daughters a mother cell produced before senescence (1). It is known that although the mother cell ages with each division, their daughters retain the same full lifespan independent of the age of the mother at least until the last few mother cell divisions (2, 3). Thus, the asymmetry in cell division leads to asymmetry of aging.Even in single-celled organisms in which cell division is seemingly morphologically symmetric, such as fission yeast or Escherichia coli, asymmetric partitioning of cellular contents can still occur and have a differential impact on the aging/death fate of the two offspring (4-8). Asymmetric cell division is also a general phenomenon in mammalian cells (e.g., during development or in mitotically active tissues), where cell division typically leads to two cells with distinct fates, often with different replicative potential. It has been argued...

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supporting

confidence: 75%

Systematic analysis of asymmetric partitioning of yeast proteome between mother and daughter cells reveals “aging factors” and mechanism of lifespan asymmetry

Yang

McCormick

Zheng

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Integral plasma membrane proteins that are preferentially retained in mother cells have been previously identified (35,36). The mechanism underlying this asymmetry remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…We designate these proteins as LARPs. Although very long-lived or mother-retained proteins have been previously identified in budding yeast (34)(35)(36)(37), the combination of these properties in the LARPs represents a class of proteins that has not been specifically investigated. We suggest that LARPs play a role in age-associated phenotypes as a yeast mother cell transits through repeated asymmetric cell divisions.…”

Section: Discussionmentioning

confidence: 99%

Identification of long-lived proteins retained in cells undergoing repeated asymmetric divisions

Thayer

Leverich

Fitzgibbon

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Long-lived proteins have been implicated in age-associated decline in metazoa, but they have only been identified in extracellular matrices or postmitotic cells. However, the aging process also occurs in dividing cells undergoing repeated asymmetric divisions. It was not clear whether long-lived proteins exist in asymmetrically dividing cells or whether they are involved in aging. Here we identify long-lived proteins in dividing cells during aging using the budding yeast, Saccharomyces cerevisiae. Yeast mother cells undergo a limited number of asymmetric divisions that define replicative lifespan. We used stable-isotope pulse-chase and total proteome mass-spectrometry to identify proteins that were both long-lived and retained in aging mother cells after ∼18 cells divisions. We identified ∼135 proteins that we designate as long-lived asymmetrically retained proteins (LARPS). Surprisingly, the majority of LARPs appeared to be stable fragments of their original fulllength protein. However, 15% of LARPs were full-length proteins and we confirmed several candidates to be long-lived and retained in mother cells by time-lapse microscopy. Some LARPs localized to the plasma membrane and remained robustly in the mother cell upon cell division. Other full-length LARPs were assembled into large cytoplasmic structures that had a strong bias to remain in mother cells. We identified age-associated changes to LARPs that include an increase in their levels during aging because of their continued synthesis, which is not balanced by turnover. Additionally, several LARPs were posttranslationally modified during aging. We suggest that LARPs contribute to age-associated phenotypes and likely exist in other organisms.ACD | asymmetric cell division | RITE | recombination-induced tag exchange | replicative aging

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“…Asymmetric partitioning of developmental molecules, including ABC transporters, is likely to be essential for controlling cellular trajectory. For example, budding in yeast results in a short-lived mother cell that retains its original transporters and a long-lived daughter cell that inherits newly synthesized transporters (Eldakak et al, 2010). This mechanism acts like a clock, whereby the newly synthesized transporters reset the mitotic age of the buds.…”

Section: Discussionmentioning

confidence: 99%

Programmed reduction of ABC transporter activity in sea urchin germline progenitors

Campanale

Hamdoun

2012

Development

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There was an error published in Development 139, 783-792.The left and right designations were inadvertently switched in Fig. 7. In Fig. 7C, the y-axis should refer to the right, not left, coelomic pouch. The corrected Fig. 7 legend is shown below. In addition, on p. 789 (lines 46 and 50) and p. 790 (line 58), where a 3/5 left-right distribution is referred to, the correct designation should be 5/3 left-right. The authors apologise to readers for this mistake.

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Asymmetrically inherited multidrug resistance transporters are recessive determinants in cellular replicative ageing

Cited by 43 publications

References 30 publications

Systematic analysis of asymmetric partitioning of yeast proteome between mother and daughter cells reveals “aging factors” and mechanism of lifespan asymmetry

Systematic analysis of asymmetric partitioning of yeast proteome between mother and daughter cells reveals “aging factors” and mechanism of lifespan asymmetry

Identification of long-lived proteins retained in cells undergoing repeated asymmetric divisions

Programmed reduction of ABC transporter activity in sea urchin germline progenitors

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