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Shedding of N-acetylglucosaminyltransferase-V is regulated by maturity of cellular N-glycan

2022; Nature Portfolio; Volume: 5; Issue: 1 Linguagem: Inglês

10.1038/s42003-022-03697-y

2399-3642

Tetsuya Hirata, Misaki Takata, Yuko Tokoro, Miyako Nakano, Yasuhiko Kizuka,

Peptidase Inhibition and Analysis

Abstract The number of N -glycan branches on glycoproteins is closely related to the development and aggravation of various diseases. Dysregulated formation of the branch produced by N -acetylglucosaminyltransferase-V (GnT-V, also called as MGAT5) promotes cancer growth and malignancy. However, it is largely unknown how the activity of GnT-V in cells is regulated. Here, we discover that the activity of GnT-V in cells is selectively upregulated by changing cellular N -glycans from mature to immature forms. Our glycomic analysis further shows that loss of terminal modifications of N -glycans resulted in an increase in the amount of the GnT-V-produced branch. Mechanistically, shedding (cleavage and extracellular secretion) of GnT-V mediated by signal peptide peptidase-like 3 (SPPL3) protease is greatly inhibited by blocking maturation of cellular N -glycans, resulting in an increased level of GnT-V protein in cells. Alteration of cellular N -glycans hardly impairs expression or localization of SPPL3; instead, SPPL3-mediated shedding of GnT-V is shown to be regulated by N -glycans on GnT-V, suggesting that the level of GnT-V cleavage is regulated by its own N -glycan structures. These findings shed light on a mechanism of secretion-based regulation of GnT-V activity.