A conserved acetylation switch enables pharmacological control of tubby-like protein stability.

Evan M Kerek, Kevin H Yoon, Shu Y Luo, Jerry Chen, Robert Valencia, Olivier Julien, Andrew J Waskiewicz, Basil P Hubbard

The Journal of biological chemistry 2021 Jan-Jun

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Tubby-like proteins (TULPs) are characterized by a conserved C-terminal domain that binds phosphoinositides. Collectively, mammalian TULP1-4 proteins play essential roles in intracellular transport, cell differentiation, signaling, and motility. Yet, little is known about how the function of these proteins is regulated in cells. Here, we present the protein-protein interaction network of TULP3, a protein that is responsible for the trafficking of G-protein-coupled receptors to cilia and whose aberrant expression is associated with severe developmental disorders and polycystic kidney disease. We identify several protein interaction nodes linked to TULP3 that include enzymes involved in acetylation and ubiquitination. We show that acetylation of two key lysine residues on TULP3 by p300 increases TULP3 protein abundance and that deacetylation of these sites by HDAC1 decreases protein levels. Furthermore, we show that one of these sites is ubiquitinated in the absence of acetylation and that acetylation inversely correlates with ubiquitination of TULP3. This mechanism is evidently conserved across species and is active in zebrafish during development. Finally, we identify this same regulatory module in TULP1, TULP2, and TULP4 and demonstrate that the stability of these proteins is similarly modulated by an acetylation switch. This study unveils a signaling pathway that links nuclear enzymes to ciliary membrane receptors via TULP3, describes a dynamic mechanism for the regulation of all tubby-like proteins, and explores how to exploit it pharmacologically using drugs. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Evan M Kerek, Kevin H Yoon, Shu Y Luo, Jerry Chen, Robert Valencia, Olivier Julien, Andrew J Waskiewicz, Basil P Hubbard. A conserved acetylation switch enables pharmacological control of tubby-like protein stability. The Journal of biological chemistry. 2021 Jan-Jun;296:100073