Reduced sphingolipid biosynthesis modulates proteostasis networks to enhance longevity

Nathaniel L. Hepowit, Eric Blalock, Sangderk Lee, Kimberly M. Bretland, Jason A. MacGurn, Robert C. Dickson

Research output: Contribution to journalArticlepeer-review


As the elderly population increases, chronic, age-associated diseases are challenging healthcare systems around the world. Nutrient limitation is well known to slow the aging process and improve health. Regrettably, practicing nutrient restriction to improve health is unachievable for most people. Alternatively, pharmacological strategies are being pursued including myriocin which increases lifespan in budding yeast. Myriocin impairs sphingolipid synthesis, resulting in lowered amino acid pools which promote entry into a quiescent, long-lived state. Here we present transcriptomic data during the first 6 hours of drug treatment that improves our mechanistic understanding of the cellular response to myriocin and reveals a new role for ubiquitin in longevity. Previously we found that the methionine transporter Mup1 traffics to the plasma membrane normally in myriocin-treated cells but is not active and undergoes endocytic clearance. We now show that UBI4, a gene encoding stressed-induced ubiquitin, is vital for myriocin-enhanced lifespan. Furthermore, we show that Mup1 fused to a deubiquitinase domain impairs myriocin-enhanced longevity. Broader effects of myriocin treatment on ubiquitination are indicated by our finding of a significant increase in K63-linked ubiquitin polymers following myriocin treatment. Although proteostasis is broadly accepted as a pillar of aging, our finding that ubiquitination of an amino acid transporter promotes longevity in myriocin-treated cells is novel. Addressing the role of ubiquitination/deubiquitination in longevity has the potential to reveal new strategies and targets for promoting healthy aging.

Original languageEnglish
Pages (from-to)472-491
Number of pages20
Issue number2
StatePublished - 2023

Bibliographical note

Funding Information:
Research reported herein was supported by the National Institute on Aging of the National Institutes of Health under Award Number R56AG024377 (RCD) and the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R35GM144112 (JAM). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2023 Hepowit et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


  • amino acid transport
  • longevity
  • proteostasis
  • sphingolipid
  • ubiquitin

ASJC Scopus subject areas

  • Aging
  • Cell Biology


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