The GCP16-zDHHC9 S-acyltransferase complex : reciprocal effects on protein S-acylation and stability

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Allagioti, Despoina and Thompson, Andrew J. and Al-Mhadeen, Mohammad A. and Lemonidis, Kimon and Salaun, Christine and Tomkinson, Nicholas C. O. and Hannoush, Rami N. and Bamji, Shernaz X. and Chamberlain, Luke H. (2026) The GCP16-zDHHC9 S-acyltransferase complex : reciprocal effects on protein S-acylation and stability. Journal of Biological Chemistry, 302 (9). 113349. ISSN 1083-351X (https://doi.org/10.1016/j.jbc.2026.113349)

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Abstract

S-Acylation is catalyzed by a family of twenty-three zinc-dependent zDHHC enzymes. A subset of these enzymes is regulated by accessory proteins, such as GCP16, which associates with the Golgi-localized acyltransferase zDHHC9 to form a functional complex. However, the specific bidirectional effects of the zDHHC9-GCP16 interaction in mammalian cells are not well defined. The S-acylation of both zDHHC9 and GCP16 is important for the activity of the acyltransferase complex. Here, we show that GCP16 enhances both the S-acylation and stability of zDHHC9, but does not affect another Golgi enzyme, zDHHC3. In addition, zDHHC9 mediates a reciprocal enhancement of the S-acylation and stability of GCP16. Similar effects on GCP16 are seen with zDHHC3, suggesting that increased S-acylation stabilizes GCP16. The S-acylated cysteines in GCP16 are present in a mostly hydrophobic region containing the α2′ and α3′ helices. This protein region appears to be linked to rapid proteasomal degradation and may become stabilized by S-acylation. GCP16 proteins with amino acid substitutions in the zDHHC9 binding interfaces confirmed the importance of complex formation for the bidirectional effects on S-acylation and stability. Furthermore, GCP16 with substitutions in the zDHHC9 binding interface did not support dendritic growth in hippocampal neurons, highlighting the functional importance of the intact complex. Overall, this study provides new insights into the bidirectional regulation of zDHHC9-GCP16 and reveals a role for S-acylation in protecting GCP16 from premature degradation. These effects may ensure that stable, functional and fully S-acylated zDHHC9-GCP16 complexes predominate at the Golgi over less stable noncomplexed zDHHC9 and GCP16.

ORCID iDs

Allagioti, Despoina, Thompson, Andrew J., Al-Mhadeen, Mohammad A., Lemonidis, Kimon ORCID logoORCID: https://orcid.org/0000-0003-1332-6002, Salaun, Christine ORCID logoORCID: https://orcid.org/0000-0003-3002-6810, Tomkinson, Nicholas C. O. ORCID logoORCID: https://orcid.org/0000-0002-5509-0133, Hannoush, Rami N., Bamji, Shernaz X. and Chamberlain, Luke H. ORCID logoORCID: https://orcid.org/0000-0002-8701-4995;
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