The lysosome is an essential organelle responsible for the digestion and recycling of materials delivered by endocytosis and autophagy. It also plays important roles in nutrient sensing and control of cell growth by regulating the localization and activity of mTORC1 signaling complex. Because of its importance, lysosome dysfunction leads to ~ 50 types of lysosomal storage diseases (LSDs) and contributes to many aging-related neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's diseases. Despite exhaustive research on how proteins are delivered to lysosomes, how lysosomes regulate their own membrane proteins remains poorly understood. However, studying this question will reveal how cells maintain a healthy lysosome during stresses and aging. Our long-term goal is to understand these fundamental questions using both yeast and mammalian cells as model systems. Recently, we discovered a ubiquitin- and ESCRT- dependent down-regulation pathway for lysosome (vacuole) membrane proteins in yeast. Follow-up investigations in our laboratory led us to hypothesize that the ubiquitin- and ESCRT- dependent degradation pathway is a general conserved mechanism to regulate the lysosome membrane composition from yeast to human. Consistently, recent proteomic studies identified multiple E3 ubiquitin ligases on the human lysosome membrane. Furthermore, the ESCRT machinery was shown to be recruited to the human lysosome membrane. In this proposed research, we plan to expand our initial findings by pursuing three specific aims.
Our Aim 1 will investigate how TORC1 regulates the vacuole membrane proteome via the ubiquitin- and ESCRT-dependent pathway in yeast.
Our Aim 2 will study how yeast vacuole membrane E3 ligases recognize their membrane substrates at both structure and function level.
Our Aim 3 will study how human lysosomes turnover their membrane proteins. Our research will shed light on the development of new treatment strategies for LSDs and lysosome-related neurodegenerative diseases.

Public Health Relevance

This proposed study will investigate the molecular mechanisms of lysosome membrane protein regulation and quality control. Lysosome dysfunction leads to lysosomal storage diseases (LSD, ~50 in humans) and contributes to aging-related neurodegenerative diseases. Our discoveries will shed lights on the development of new treatment strategies for LSDs and neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM133873-02
Application #
10018043
Study Section
Membrane Biology and Protein Processing Study Section (MBPP)
Program Officer
Maas, Stefan
Project Start
2019-09-13
Project End
2024-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109