Research

We study mechanisms of protein trafficking and degradation, which are critical for the maintenance of protein homeostasis and subcellular organization. These processes are essential for maintaining healthy cells and tissues, and their breakdown contributes to the progression of disease and aging.

Regulation of Cell Growth & Metabolism by Endocytosis

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The Role of Sphingolipid Metabolism in Aging

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MacGurn Lab At Work

Regulation of Cell Growth and Metabolism by Endocytosis

All cells must adapt to their surroundings to survive. Our research in the MacGurn Lab explores the core mechanisms behind this adaptive process, specifically focusing on how cells are remodeled via membrane trafficking and protein degradation. By understanding this fundamental biology, we hope to find new ways to combat disease. Some important fundamental questions that motivate our research include:

  • How do cells sense nutrient availability and convert these signals into programs for growth or stress?
  • How is transporter trafficking coordinated with cell signaling, metabolism, and growth decisions?
  • How do endocytic processes interface with other complex cellular systems like metabolism and translation?

One lab project is focused on understanding how glucose transporters undergo regulated endocytosis. GLUT1 is responsible for glucose uptake in many human cells and tissues, yet very little is known about their regulation in a cellular context. Dissecting mechanisms that regulate GLUT1 subcellular localization and trafficking will have important implications for human diseases ranging from cancer to GLUT1 Deficiency Syndrome.

Recent Publication:

Qualls-Histed SJ, Nielsen CP, MacGurn JA. Lysosomal trafficking of the glucose transporter GLUT1 requires sequential regulation by TXNIP and ubiquitin. iScience. 2023 Feb 6;26(3):106150. doi: 10.1016/j.isci.2023.106150. eCollection 2023 Mar 17. PMID: 36890792.

Another lab project is focused on understanding how endocytic trafficking of amino acid transporters is coordinated with changes in cell growth and metabolism. Our work has identified important relationships between endocytosis and key signaling pathways for growth and stress. These experiments will address mechanisms that couple endocytosis to other complex cellular processes including protein translation, stress signaling, and growth decisions.

Recent Preprint:

Hepowit NL, Singkhek HL, Frazier KD, Johnson DJ, MacGurn JA. Methionine-triggered growth arrest reveals activation of Gcn2 by methionine transporter endocytosis. bioRxiv. 2025. doi: 10.1101/2025.05.12.653625.

The Role of Sphingolipid Metabolism in Aging

Aging is associated with the gradual breakdown of biological systems and increased susceptibility to diseases, including neurodegeneration and cardiovascular disease. There is an emerging consensus that interventions that decrease sphingolipids (SLs) improve longevity and healthspan, although the mechanistic basis for these benefits is not well-defined. We seek to define these mechanisms, with the long-term goal of identifying novel pathways and therapeutic targets related to aging. Some important fundamental questions that motivate our research include:
  • How does sphingolipid depletion increase longevity and healthspan in various aging models?
  • How does sphingolipid composition and subcellular distribution change in aging cells and tissues?
  • What are the mechanisms coupling sphingolipid metabolism and mitochondria function?
One project in our lab is focused on understanding how sphingolipid depletion impacts membrane trafficking. Our data shows that this process regulates the stability and trafficking of nutrient transporters at the cell surface. These findings reveal how changes in sphingolipid metabolism trigger remodeling of the plasma membrane proteome, ultimately affecting cell growth and metabolism.

Recent Publication:

Hepowit NL, Moon B, Ebert AC, Dickson RC, MacGurn JA. Art2 mediates selective endocytosis of methionine transporters during adaptation to sphingolipid depletion. J Cell Sci. 2023 Jul 15;136(14):jcs260675. doi: 10.1242/jcs.260675. Epub 2023 Jul 25. PMID: 37337792.

Another project investigates the critical link between sphingolipid metabolism and mitochondrial function during cellular aging and stress. We’ve found that sphingolipid levels are directly coupled to changes in mitochondrial morphology and overall health. Uncovering the molecular basis of this relationship has the potential to reveal novel therapeutic targets for age-related diseases and stress-induced conditions.

Recent Preprint:

Ebert AC, Hepowit NL, Martinez TA, Vollmer H, Singkhek HL, Frazier KD, Kantejeva SA, Patel MR, MacGurn JA. Sphingolipid metabolism drives mitochondria remodeling during aging and oxidative stress. bioRxiv. 2025. doi: 10.1101/2025.02.26.640157.