Date of Award

4-21-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Applied Science

First Advisor

Fusheng Tang

Abstract

The late endosome (LE) is a hub organelle connecting endocytic, biosynthetic, exocytotic, and autophagic vesicle traffic pathways. Malfunctions of LEs are associated with multiple age dependent diseases such as Parkinson’s disease (PD). Despite this significance, how cells refurbish lipids and proteins to LEs to maintain their sustained activities are not clear. Previous studies in the model organism budding yeast show that up-regulation of a lipid transporter Osh6 (PERG6-OSH6) accumulates phosphatidylinositol-4-phosphate (PI4P) on the trans-Golgi network. It also promotes vacuole fusion and maintains the robustness of vacuoles in aged cells. Since LEs are the organelle between the TGN and vacuoles in multiple vesicle trafficking pathways, I employed this longevity mutant to explore the contribution of different pathways to the dynamics of LEs. I compared the traffic of endocytosed DNA, the localization of the plasma membrane proton ATPase Pma1, and the secretion of a vacuolar protease carboxypeptidase Y (CPY) of PERG6-OSH6 in combination of more than 10 mutants defective in different traffic pathways between TGN and vacuoles, finding several novel results. First, PERG6-OSH6 decreased transformation, the traffic of endocytosed DNA from Golgi to the nucleus, in a PI4P dependent manner. Second, PERG6-OSH6 increased the transport of Pma1 from the TGN to LE and then vacuoles. Third, PERG6-OSH6 stimulated an unconventional secretion originating from the LE in a TGN-to-LE dependent manner. These observations suggest that the accumulated PI4P on the TGN in PERG6-OSH6 increases TGN-to-LE vesicle traffic and provides fresh lipids/proteins to achieve functions of LEs. This work provides a roadmap for further studies on molecular mechanisms of PD due to the conservation of yeast proteins (Osh6, Vps74, Vps35, Ypt7, Gtr1) in this study.

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