PUBLICATION
A conserved acetylation switch enables pharmacological control of tubby-like protein stability
- Authors
- Kerek, E.M., Yoon, K.H., Luo, S.Y., Chen, J., Valencia, R., Julien, O., Waskiewicz, A.J., Hubbard, B.P.
- ID
- ZDB-PUB-201120-123
- Date
- 2020
- Source
- The Journal of biological chemistry 296: 100073 (Journal)
- Registered Authors
- Waskiewicz, Andrew
- Keywords
- Cullin-3, E1A binding protein p300 (P300), E3 ubiquitin ligase, Histone deacetylases (HDACs), TULP3, Tubby-like proteins (TULPs), acetylation, histone acetyltransferases (HATs), histone deacetylase 1 (HDAC1), post-translational modification (PTM)
- MeSH Terms
-
- Acetylation
- Eye Proteins/genetics
- Eye Proteins/metabolism*
- HEK293 Cells
- HeLa Cells
- Histone Deacetylase 1/genetics
- Histone Deacetylase 1/metabolism
- Humans
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism*
- Protein Stability
- p300-CBP Transcription Factors/genetics
- p300-CBP Transcription Factors/metabolism*
- PubMed
- 33187986 Full text @ J. Biol. Chem.
Citation
Kerek, E.M., Yoon, K.H., Luo, S.Y., Chen, J., Valencia, R., Julien, O., Waskiewicz, A.J., Hubbard, B.P. (2020) A conserved acetylation switch enables pharmacological control of tubby-like protein stability. The Journal of biological chemistry. 296:100073.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping