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Summer 2023
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2023-08
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The Endoplasmic reticulum (ER) membrane lipid raft-associated proteins erlin 1 (E1) and erlin2 (E2) are ~40 kDa proteins, and they are members of a superfamily of stomatin/prohibitin/ flotillin/HflK/C (SPFH) domain-containing proteins. E1 and E2 form a massive (~2 MDa) hetero-oligomeric complex that is an essential mediator of inositol 1,4,5-trisphosphate receptor (IP3R) ubiquitination and degradation. Mutations of E1 and E2 are involved in many pathological processes in neurological disorders, such as Hereditary Spastic Paraplegia (HSP), with unknown molecular mechanisms. The Wojcikiewicz laboratory has previously provided evidence that the erlin complex, immunopurified from mammalian cells binds to phosphatidylinositol 3-phosphate (PI(3)P), a key player in membrane dynamics and trafficking regulation in endocytosis and autophagy. In addition, the erlin complex may be involved in different cellular processes beyond IP3Rs degradation, but the exact nature of these roles has remained elusive. My research described in this thesis has uncovered intriguing new insights into the erlin complex and its role in previously unknown aspects of cellular biology. Through the application of diverse biochemical and molecular biology assays, I successfully identified specific regions on E2 that are essential for its binding to PI(3)P. Additionally, my research revealed that the erlin complex plays an important role in regulating cellular PI(3)P levels through its interaction and stabilization with this lipid. This binding and stabilization of PI(3)P are crucial for the regulation of autophagy and lysosome function. These findings contribute to our understanding of the erlin complex's importance in cellular biology and provide valuable knowledge about related processes that have implications for human health and disease.