Date of Award

January 2026

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Jonathan Bogan

Abstract

Glucose uptake in adipocytes and myocytes depend on the regulated trafficking of the insulin-responsive glucose transporter GLUT4. In the absence of insulin, GLUT4 is sequestered in intracellular compartments known as GLUT4 storage vesicles (GSVs). Upon insulin stimulation, these vesicles rapidly translocate to and fuse with the plasma membrane to allow glucose uptake by the cell. A key regulator of this process is TUG (Tether containing UBX domain for GLUT4). TUG acts as a molecular tether that retains GSVs intracellularly, preventing their premature delivery to the plasma membrane. Insulin signaling triggers site-specific proteolytic cleavage of TUG, causing the release of GSVs from their intracellular anchoring site and enabling their trafficking along cytoskeletal tracks to the plasma membrane. This regulated release ensures a rapid increase in cell-surface GLUT4, thereby facilitating glucose uptake following meals.

Tankyrase (TNKS), a member of the poly(ADP-ribose) polymerase (PARP) family, regulates GLUT4 trafficking and stability. Previous work in the Bogan laboratory show that TNKS interacts with TUG. Like other PARP family members, TNKS is known to catalyze the poly(ADP-ribosyl)ation (PARylation) of target proteins to modulate their stability, interactions, and cellular localization. More pertinent to this discussion, tankyrase has been shown to promote phase separation of proteins to form biomolecular condensates. In the context of glucose uptake, the formation of biomolecular condensates is likely necessary to increase TUG sequestration of GSVs, allowing more GLUT4 to be trafficked to the plasma membrane upon insulin stimulation.

Understanding the mechanism by which TUG regulates GSVs retention and mobilization, and what role tankyrase plays in this process would have important implications for Type 2 diabetes, a disease characterized by impaired insulin-stimulated GLUT4 translocation. In this study, we tested whether TUG can be PARylated by tankyrase. We show that TUG is PARylated in the presence of tankyrase, and that mutation of the putative PARylated residue, S538, in TUG prevents this modification.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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