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Selective targeting of non-centrosomal AURKA functions through use of a targeted protein degradation tool

Published version
Peer-reviewed

Change log

Authors

Wang, Richard 
Ascanelli, Camilla 
Abdelbaki, Ahmed 
Rasmusson, Tim 

Abstract

Abstract: Targeted protein degradation tools are becoming a new therapeutic modality, allowing small molecule ligands to be reformulated as heterobifunctional molecules (PROteolysis Targeting Chimeras, PROTACs) that recruit ubiquitin ligases to targets of interest, leading to ubiquitination and destruction of the targets. Several PROTACs against targets of clinical interest have been described, but detailed descriptions of the cell biology modulated by PROTACs are missing from the literature. Here we describe the functional characterization of a PROTAC derived from AURKA inhibitor MLN8237 (alisertib). We demonstrate efficient and specific destruction of both endogenous and overexpressed AURKA by Cereblon-directed PROTACs. At the subcellular level, we find differential targeting of AURKA on the mitotic spindle compared to centrosomes. The phenotypic consequences of PROTAC treatment are therefore distinct from those mediated by alisertib, and in mitotic cells differentially regulate centrosome- and chromatin- based microtubule spindle assembly pathways. In interphase cells PROTAC-mediated clearance of non-centrosomal AURKA modulates the cytoplasmic role played by AURKA in mitochondrial dynamics, whilst the centrosomal pool is refractory to PROTAC-mediated clearance. Our results point to differential sensitivity of subcellular pools of substrate, governed by substrate conformation or localization-dependent accessibility to PROTAC action, a phenomenon not previously described for this new class of degrader compounds.

Description

Funder: AstraZeneca; doi: https://doi.org/10.13039/100004325

Keywords

Article, /631/1647, /631/80, /631/92, /631/154, /14, /14/35, /14/1, /13, /13/109, article

Journal Title

Communications Biology

Conference Name

Journal ISSN

2399-3642

Volume Title

4

Publisher

Nature Publishing Group UK
Sponsorship
RCUK | Biotechnology and Biological Sciences Research Council (BBSRC) (1804956, BB/R004137/1)