MYPT1 O-GlcNAc modification regulates sphingosine-1-phosphate mediated contraction.

Nichole J Pedowitz, Anna R Batt, Narek Darabedian, Matthew R Pratt

Nature chemical biology 2021 Feb

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Many intracellular proteins are modified by N-acetylglucosamine, a post-translational modification termed O-GlcNAc. This modification is found on serine and threonine side chains and has the potential to regulate signaling pathways through interplay with phosphorylation. Here, we discover and characterize one such example. We find that O-GlcNAc levels control the sensitivity of fibroblasts to actin contraction induced by the signaling lipid sphingosine-1-phosphate (S1P), culminating in the phosphorylation of myosin light chain (MLC) and cellular contraction. Specifically, O-GlcNAc modification of the phosphatase subunit MYPT1 inhibits this pathway by blocking MYPT1 phosphorylation, maintaining its activity and causing the dephosphorylation of MLC. Finally, we demonstrate that O-GlcNAc levels alter the sensitivity of primary human dermal fibroblasts in a collagen-matrix model of wound healing. Our findings have important implications for the role of O-GlcNAc in fibroblast motility and differentiation, particularly in diabetic wound healing.

Citation

Nichole J Pedowitz, Anna R Batt, Narek Darabedian, Matthew R Pratt. MYPT1 O-GlcNAc modification regulates sphingosine-1-phosphate mediated contraction. Nature chemical biology. 2021 Feb;17(2):169-177