Bibliographic Details
| Title: |
Targeted degradation of zDHHC-PATs decreases substrate S-palmitoylation. |
| Authors: |
Bai, Mingjie, Gallen, Emily, Memarzadeh, Sarah, Howie, Jacqueline, Gao, Xing, Kuo, Chien-Wen S., Brown, Elaine, Swingler, Simon, Wilson, Sam J., Shattock, Michael J., France, David J., Fuller, William |
| Source: |
PLoS ONE; 3/21/2024, Vol. 19 Issue 3, p1-18, 18p |
| Subject Terms: |
PALMITOYLATION, MEMBRANE proteins, CELL lines, TRANSFERASES, PROOF of concept |
| Abstract: |
Reversible S-palmitoylation of protein cysteines, catalysed by a family of integral membrane zDHHC-motif containing palmitoyl acyl transferases (zDHHC-PATs), controls the localisation, activity, and interactions of numerous integral and peripheral membrane proteins. There are compelling reasons to want to inhibit the activity of individual zDHHC-PATs in both the laboratory and the clinic, but the specificity of existing tools is poor. Given the extensive conservation of the zDHHC-PAT active site, development of isoform-specific competitive inhibitors is highly challenging. We therefore hypothesised that proteolysis-targeting chimaeras (PROTACs) may offer greater specificity to target this class of enzymes. In proof-of-principle experiments we engineered cell lines expressing tetracycline-inducible Halo-tagged zDHHC5 or zDHHC20, and evaluated the impact of Halo-PROTACs on zDHHC-PAT expression and substrate palmitoylation. In HEK-derived FT-293 cells, Halo-zDHHC5 degradation significantly decreased palmitoylation of its substrate phospholemman, and Halo-zDHHC20 degradation significantly diminished palmitoylation of its substrate IFITM3, but not of the SARS-CoV-2 spike protein. In contrast, in a second kidney derived cell line, Vero E6, Halo-zDHHC20 degradation did not alter palmitoylation of either IFITM3 or SARS-CoV-2 spike. We conclude from these experiments that PROTAC-mediated targeting of zDHHC-PATs to decrease substrate palmitoylation is feasible. However, given the well-established degeneracy in the zDHHC-PAT family, in some settings the activity of non-targeted zDHHC-PATs may substitute and preserve substrate palmitoylation. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
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