CHARACTERIZATION OF THE ROLE OF K63-LINKED UBIQUITINATION IN PROTEIN AND MITOCHONDRIAL HOMEOSTASIS: IMPLICATIONS FOR PARKINSON'S DISEASE

Abstract

Poly-ubiquitin modification usually targets proteins for proteasomal degradation. However, K63-linked chain is atypical as it is uncoupled from the proteasome. Here, I sought to clarify the role of this non-canonical form of ubiquitination in protein and mitochondrial homeostasis. I showed that during proteasome dysfunction, K63-polyubiquitination is enhanced and parkin is a key enzyme involved. Mechanistically, the phenomenon occurs as a result of increased affinity of parkin for Ubc13 (an E2 that mediates K63-polyubiquitination exclusively), which appears to facilitate the autophagic clearance of substrates and as such promotes cellular survival in times of proteolytic stress. Separately, I showed that K63-polyubiquitination can participate in mitochondrial homeostasis by regulating the expression of a cleaved form of PINK1 which is otherwise rapidly degraded. I have also identified the pathway involved in this. Taken together, my study has expanded the role of K63-polyubiquitination to include its participation in protein and mitochondrial homeostasis.