Date of Award

4-24-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Fusheng Tang

Abstract

The target of rapamycin complex 1 (TORC1) is a master regulator of cell growth as well as a negative regulator of longevity. A recent study in yeast showed that the vacuolar TORC1 stimulates protein synthesis and cell growth while the endosomal TORC1 inhibits autophagy, a pro-longevity process. Since late endosome frequently exchanges membranes with vacuoles, the spatial dissection of TORC1 raises an interesting question as to how to inhibit the endosomal TORC1 and boosts the vacuolar TORC1 to extend the health span. In my thesis, I employed a longevity mutant that mildly up-regulates Osh6 (PERG6-OSH6) to address this question. I found that PERG6-OSH6 had strong polarized actin patches and delayed initiation of endocytosis, two parameters apparently associated with down-regulation of TORC1. However, Perg6-OSH6 increased the cell size in a Gtr1-dependent manner. Gtr1 activates TORC1 through traveling along the trans-Golgi network (TGN) to late endosome (LE) trafficking pathway. In addition to Gtr1, the cell size effect was also dependent on Gga2, a protein that initiates the TGN-LE trafficking. Thus, the dependency of PERG6-OSH6 on Gga2 and Gtr1 suggests that up-regulation of Osh6 may activate vacuolar TORC1 via the TGN-LE pathway. Further analyses of the TGN-LE pathway suggests that both anterograde and retrograde trafficking of this pathway are crucial for PERG6-OSH6’s effects on the trafficking of Pma1. Based on these observations, I propose a new mechanism to extend the health span. Up-regulation of Osh6 accelerates TGN-LE trafficking especially the retrograde trafficking and decreases the size of late endosome. This decrease in LE size limits the assembly of the endosomal TORC1 while facilitates the assembly of the vacuolar TORC1.

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