S-Palmitoylation stabilizes OGT and the OGT-PPP1CC complex
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…
O-linked beta-N-acetylglucosamine (O-GlcNAc) transferase, known as OGT, is responsible for adding O-GlcNAc to thousands of proteins within cells. However, researchers have found that OGT itself undergoes a modification called S-palmitoylation at two specific sites, Cys-472 and Cys-477. This modification is facilitated by a protein called zDHHC14 and undone by another enzyme called acyl protein thioesterase 2 (APT2).
The study reveals that S-palmitoylation helps stabilize OGT, keeping it away from a lysosomal pathway called CMA. This stabilization is achieved by reducing the interaction between OGT and a chaperone protein called HSC70. Additionally, S-palmitoylation increases the binding affinity between OGT and a protein called PPP1CC, although it does not affect another PPP1CC variant, PPP1CB.
The researchers further discovered that S-palmitoylation enhances the interaction between OGT and Yes-associated protein-1 (YAP), a protein that works with PPP1CC. As a result, this modification boosts O-GlcNAcylation, a process that modifies YAP. The findings highlight the importance of S-palmitoylation and the CMA-mediated breakdown of lysosomal OGT in fine-tuning the activity of key OGT complexes, such as OGT-PPP1CC. This mechanism also contributes to the selective targeting of OGT substrates.
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