Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Shelley L. Berger

Abstract

Autophagy is an evolutionally conserved membrane trafficking process that degrades unwanted proteins, organelles and exogenous pathogens through autophagosomes and lysosomes. In mammals, dysfunction of autophagy machinery is associated with a number of diseases and pathologies. While the majority of autophagy studies focus on its function in maintaining protein homeostasis in the cytoplasm, the role of autophagy in the nucleus is less known. In the first part of my dissertation research, I have explored the mechanism of autophagy in degrading nuclear lamina. We show that a key autophagy protein, LC3, associates with nuclear lamina protein Lamin B1 and chromatin, and mediates the translocation of Lamin B1 and associated chromatin fragments to the cytoplasm for degradation during cellular senescence. This study provides new insight into the nuclear function of mammalian autophagy pathway. With the initial understanding of the nuclear autophagy pathway, in the second part of my dissertation, I have investigated the mechanism underlying the loss of SIRT1, a critical nuclear regulator of cell metabolism and aging, in the context of cellular senescence and in vivo aging. We demonstrate that nuclear SIRT1 is degraded through autophagy machinery in senescent human fibroblasts and certain tissues of aged mice. During senescence, SIRT1 is recognized as an autophagy substrate and undergoes nucleus-to-cytoplasm transportation. The autophagy protein LC3 interacts with SIRT1 to facilitate its degradation process, while disruption of LC3-SIRT1 association rescues SIRT1 downregulation. Moreover, SIRT1 is downregulated in aged mouse spleen, testis and hematopoietic stem and progenitor cells through lysosomal degradation. Given the important roles of SIRT1 in metabolism and aging, this study sheds light on a potential strategy to maintain SIRT1 protein levels to improve SIRT1 function and promote healthy lifespan. Overall, my dissertation studies characterize two major nuclear substrates of the autophagy pathway, contribute to our knowledge in the nuclear aspect of mammalian autophagy machinery and sirtuin biology, and suggest a new perspective in pharmaceutical design of anti-aging compounds.

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