Date of Award
Doctor of Philosophy (PhD)
Multisystem proteinopathy (MSP) defines a spectrum of degenerative diseases unified by TDP-43 pathology that affect muscle, brain and bone. Mutations in several proteins (VCP, p62/SQSTM1, HNRNPA2B1, HNRNPA1) can all cause MSP via impairments in autophagic protein degradation (VCP and SQSTM1) or RNA granule dynamics (HNRNPA2B1 and HNRNPA1). Phenotypically, MSP mutations lead to variable penetrance of several phenotypes: Paget’s disease of the bone (PDB), rimmed vacuolar inclusion body myopathy (RV-IBM), amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). However, how a same mutation of a protein can develop different diseases remains unclear. Understanding of p62/SQSTM1 (SQSTM1) function is critical to answer this question. In this dissertation, we provide evidence that SQSTM1 is regulated via its UBA domain ubiquitination. We find that Keap1/Cullin3 ubiquitinates SQSTM1 at lysine 420 within its UBA domain. Substitution of lysine 420 with arginine or disease-associated mutation of SQSTM1 disrupts its ubiquitination, sequestering activity, and degradation. In contrast, overexpression of Keap1/Cullin3 in SQSTM1-WT expressing cells increases ubiquitinated inclusion formation, SQSTM1’s association with autophagosomes and rescues proteotoxicity.
We also provide evidence that the oligogenic inheritance of a disease associated SQSTM1 mutation with a rare coding variant in the low-complexity domain (LCD) of the RNA-binding protein, TIA1 (p.N357S) can dictate a myodegenerative phenotypes. Deletion or mutation of SQSTM1 along with TIA1 disease mutants synergistically impairs RNA stress granules clearance and their dynamics. These findings demonstrate a pathogenic connection between SG homeostasis and ubiquitin mediated autophagic degradation that defines the penetrance of a MSP phenotype.
Chair and Committee
Abhinav Diwan, Phyllis Hanson, Timothy Miller, Heather True,
Lee, Eugene, "The Ugly Sequestosome1:the role of p62/SQSTM1 in autophagy and multisystem proteinopathy" (2018). Arts & Sciences Electronic Theses and Dissertations. 1554.