Details

Autor(en) / Beteiligte

• Goss, Alissa Campbell

Titel

TMEDs Are Differential Regulators of Mutant Membrane Proteins

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2023

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Over one-third of the human proteome is produced and processed in the secretory pathway, necessitating extensive protein handling and quality control mechanisms to maintain proteostasis. Aberrant handling of mutant secretory pathway proteins has been associated with numerous diseases that cause significant patient morbidity and mortality. However, mechanistic understanding of many of these diseases is limited, and there is a subsequent paucity of targeted therapeutics available to these patients. The work presented in this dissertation seeks to address this need by elucidating mechanisms of mutant membrane protein accumulation in disease. Specifically, we investigate the role of the TMED family of proteins in mutant membrane protein accumulation. In Chapter 2, we demonstrate that TMEDs work in complex with one another to differentially regulate the accumulation of a mutant membrane protein, MUC1-fs, that causes MUC1 kidney disease. We identify a TMED7/9/2/10 complex necessary for MUC1-fs entrapment and a TMED1 or TMED5/9/2/10 complex that allows or promotes MUC1-fs degradation. In Chapter 3, we demonstrate that small molecule BRD7635 can disrupt the TMED7/9/2/10 entrapment complex, reducing MUC1-fs accumulation in vivo. Further, we demonstrate that TMED-targeting by BRD7635 reduces accumulation of another mutant membrane protein, Rho-P23H, in an in vivo model of retinitis pigmentosa. Our work deeply characterizes the differential regulation of diverse mutant membrane protein accumulation by TMEDs and demonstrates that small molecule targeting of the TMEDs has therapeutic potential across multiple diseases.