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Apollo - University of Cambridge Repository, 2020

DOI: 10.17863/cam.47731

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Studies on the autophagy gene WIPI4 and its interactor UBR5

Journal article published in 2020 by Ye Zhu
This paper was not found in any repository; the policy of its publisher is unknown or unclear.
This paper was not found in any repository; the policy of its publisher is unknown or unclear.

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Abstract

Autophagy is a tightly regulated process that sequesters and delivers proteins and other cellular substances for degradation in the lysosome. Dysfunction of autophagy has been implicated in many diseases including neurodegenerative diseases, cancer, and infectious diseases. Beta-propeller Protein-Associated Neurodegeneration (BPAN), an early-onset neurodegenerative disease, is caused by mutations in WIPI4, a member of the WD repeat domain phosphoinositide-interacting family. This thesis identifies WIPI4 as a regulator of the closure of autophagosomes. Although many proteins have been found to regulate the late stage of autophagosome formation, the exact mechanism of this process has remained unclear. This thesis explored the regulatory mechanism of GABARAP by WIPI4. GABARAP is a potential closure regulator and is also required for expansion and fusion steps of autophagy. I identified that WIPI4 regulates the stability and trafficking of GABARAP. Further studies identified UBR5, an N-recognin, to be a potential GABARAP-targeting E3 ligase. In WIPI4 depleted HeLa cells, there is an increased interaction between UBR5 and GABARAP. The negative regulatory activity of UBR5 on GABARAP is dependent on its E3 ligase activity. In addition, mutation of the N-degron of GABARAP reduces its ubiquitination by K48-linked chains, suggesting that GABARAP may be an N-end rule pathway substrate. Altogether, this thesis furthers our understanding of the mechanism of autophagosome closure and identifies a potential novel GABARAP E3 ligase.