S-Palmitoylation stabilizes OGT and the OGT-PPP1CC complex
- 1Capital Normal University
Abstract
O-linked {beta}-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is the sole writer for intracellular O-GlcNAcylation. It catalyzes O-GlcNAcylation of thousands of protein substrates, but relatively less is known about the post-translational modifications that occur on OGT itself. Herein, we demonstrate that OGT is S-palmitoylated at Cys-472 and Cys-477, which is mediated by the S-acyltransferase Zinc Finger DHHC-Type Palmitoyl transferase 14 (zDHHC14) and removed by acyl protein thioesterase 2 (APT2). S-Palmitoylation stabilizes OGT by shunting it away from the lysosomal chaperone-mediated autophagy (CMA) pathway, as S-palmitoylation decreases the interaction between OGT and heat shock cognate 70 kDa protein (HSC70), the CMA chaperone. Via label-free quantitative mass spectrometry, we find that S- palmitoylation elevates the affinity between OGT and protein phosphatase 1 catalytic subunit gamma (PPP1CC), but not PPP1CB. We further demonstrate that S-palmitoylation of OGT augments binding with Yes-associated protein-1 (YAP), a protein that associates with PPP1CC, and subsequently enhances YAP O-GlcNAcylation. Our work unearths S-palmitoylation of OGT and CMA-mediated degradation of lysosomal OGT, the orchestration of which finetunes the activity of key OGT complexes, such as OGT-PPP1CC, and contributes to OGT substrate selectivity.
Versions
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BibTeX
@misc{lu2026spalmitoylation,
title = {{S-Palmitoylation stabilizes OGT and the OGT-PPP1CC complex}},
author = {X. Lu and T. Xu and J. Li and Y. Liu and W. Zhou and K. Wang and C. Niu and N. Tang and L. Zhang and J. Li},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.29.747956},
url = {https://www.biorxiv.org/content/10.64898/2026.08.29.747956v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - S-Palmitoylation stabilizes OGT and the OGT-PPP1CC complex
AU - X. Lu
AU - T. Xu
AU - J. Li
AU - Y. Liu
AU - W. Zhou
AU - K. Wang
AU - C. Niu
AU - N. Tang
AU - L. Zhang
AU - J. Li
PY - 2026
DA - 2026/08/29
PB - bioRxiv
DO - 10.64898/2026.08.29.747956
UR - https://www.biorxiv.org/content/10.64898/2026.08.29.747956v1
AB - O-linked {beta}-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is the sole writer for intracellular O-GlcNAcylation. It catalyzes O-GlcNAcylation of thousands of protein substrates, but relatively less is known about the post-translational modifications that occur on OGT itself. Herein, we demonstrate that OGT is S-palmitoylated at Cys-472 and Cys-477, which is mediated by the S-acyltransferase Zinc Finger DHHC-Type Palmitoyl transferase 14 (zDHHC14) and removed by acyl protein thioesterase 2 (APT2). S-Palmitoylation stabilizes OGT by shunting it away from the lysosomal chaperone-mediated autophagy (CMA) pathway, as S-palmitoylation decreases the interaction between OGT and heat shock cognate 70 kDa protein (HSC70), the CMA chaperone. Via label-free quantitative mass spectrometry, we find that S- palmitoylation elevates the affinity between OGT and protein phosphatase 1 catalytic subunit gamma (PPP1CC), but not PPP1CB. We further demonstrate that S-palmitoylation of OGT augments binding with Yes-associated protein-1 (YAP), a protein that associates with PPP1CC, and subsequently enhances YAP O-GlcNAcylation. Our work unearths S-palmitoylation of OGT and CMA-mediated degradation of lysosomal OGT, the orchestration of which finetunes the activity of key OGT complexes, such as OGT-PPP1CC, and contributes to OGT substrate selectivity.
ER -