Developmental Glycobiology Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4370;
Department of Medical Genetics, Institute of Biomedicine.
Proc Natl Acad Sci U S A. 2014 May 20;111(20):7296-301. doi: 10.1073/pnas.1322264111. Epub 2014 May 5.
Polarized secretion is crucial in many tissues. The conserved protein modification, O-glycosylation, plays a role in regulating secretion. However, the mechanisms by which this occurs are unknown. Here, we demonstrate that an O-glycosyltransferase functions as a novel regulator of secretion and secretory vesicle formation in vivo by glycosylating the essential Golgi/endoplasmic reticulum protein, Tango1 (Transport and Golgi organization 1), and conferring protection from furin-mediated proteolysis. Loss of the O-glycosyltransferase PGANT4 resulted in Tango1 cleavage, loss of secretory granules, and disrupted apical secretion. The secretory defects seen upon loss of pgant4 could be rescued either by overexpression of Tango1 or by knockdown of a specific furin (Dfur2) in vivo. Our studies elucidate a novel regulatory mechanism whereby secretion is influenced by the yin/yang of O-glycosylation and proteolytic cleavage. Moreover, our data have broader implications for the potential treatment of diseases resulting from the loss of O-glycosylation by modulating the activity of specific proteases.
极化分泌在许多组织中至关重要。保守的蛋白质修饰——O-糖基化，在调节分泌中发挥作用。然而，其发生的机制尚不清楚。在这里，我们证明了一种 O-糖基转移酶通过糖基化必需的高尔基体/内质网蛋白 Tango1（运输和高尔基体组织 1）并赋予其免受弗林介导的蛋白水解的保护作用，作为一种新的分泌和分泌小泡形成的体内调节剂发挥作用。O-糖基转移酶 PGANT4 的缺失导致 Tango1 切割、分泌颗粒丢失和顶端分泌中断。pgant4 缺失时观察到的分泌缺陷可以通过过表达 Tango1 或体内敲低特定弗林（Dfur2）来挽救。我们的研究阐明了一种新的调节机制，即通过 O-糖基化和蛋白水解切割的阴阳影响来调节分泌。此外，我们的数据对于通过调节特定蛋白酶的活性来治疗因 O-糖基化丢失而导致的疾病具有更广泛的意义。
