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bioRxiv · 10.1101/2022.01.04.474939

PLEKHA5 regulates mitotic progression by promoting APC/C localization to microtubules

Cao, X.·Shami Shah, A.·Sanford, E. J.·Smolka, M. B.·Baskin, J. M.
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Abstract

The anaphase-promoting complex/cyclosome (APC/C) coordinates advancement through mitosis via temporally controlled polyubiquitination of effector proteins. Despite the long-appreciated spatial organization of key events in mitosis mediated largely by cytoskeletal networks, the spatial regulation of APC/C, the major mitotic E3 ligase, is poorly understood. Here, we describe a microtubule-resident protein, PLEKHA5, as an interactor of APC/C and spatial regulator of its activity in mitosis. PLEKHA5 knockdown delayed mitotic progression, causing accumulation of APC/C substrates dependent upon the PLEKHA5-APC/C interaction. To assess the spatial importance of this interaction, we developed microtubule-localized proximity biotinylation tools, which revealed that depletion of PLEKHA5 decreased the extent of APC/C association with the microtubule cytoskeleton. This decreased APC/C microtubule-localization in turn prevented efficient loading of APC/C with its co-activator CDC20, leading to defects in E3 ligase catalytic activity. We propose that PLEKHA5 functions as an adaptor of APC/C that promotes its subcellular localization to microtubules and facilitates its activation by CDC20, thus ensuring the timely turnover of key mitotic APC/C substrates and proper progression through mitosis.

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Cao, X., Shami Shah, A., Sanford, E. J., Smolka, M. B., Baskin, J. M.. 2022-01-04. PLEKHA5 regulates mitotic progression by promoting APC/C localization to microtubules. https://doi.org/10.1101/2022.01.04.474939

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