Abstract
A small portion of cellular glycogen is transported to and degraded in lysosomes by acid α-glucosidase (GAA) in mammals, but it is unclear why and how glycogen is transported to the lysosomes. Stbd1 has recently been proposed to participate in glycogen trafficking to lysosomes. However, our previous study demonstrated that knockdown of Stbd1 in GAA knock-out mice did not alter lysosomal glycogen storage in skeletal muscles. To further determine whether Stbd1 participates in glycogen transport to lysosomes, we generated GAA/Stbd1 double knock-out mice. In fasted double knock-out mice, glycogen accumulation in skeletal and cardiac muscles was not affected, but glycogen content in liver was reduced by nearly 73% at 3 months of age and by 60% at 13 months as compared with GAA knock-out mice, indicating that the transport of glycogen to lysosomes was suppressed in liver by the loss of Stbd1. Exogenous expression of human Stbd1 in double knock-out mice restored the liver lysosomal glycogen content to the level of GAA knock-out mice, as did a mutant lacking the Atg8 family interacting motif (AIM) and another mutant that contains only the N-terminal 24 hydrophobic segment and the C-terminal starch binding domain (CBM20) interlinked by an HA tag. Our results demonstrate that Stbd1 plays a dominant role in glycogen transport to lysosomes in liver and that the N-terminal transmembrane region and the C-terminal CBM20 domain are critical for this function.
Highlights
Liver and muscle are the two primary sites for glycogen metabolism in mammals
Understanding the mechanism of how glycogen is transported into lysosomes is a critical step for the exploration of new therapeutic targets for Pompe disease considering the significant limitations of enzyme replacement therapy [7,8,9]
It has been demonstrated that autophagy plays a partial role in the transport of glycogen to lysosomes in skeletal muscle of GAA-KO mice [12], which suggests that other route(s) exist for this process
Summary
Starch Binding Domaincontaining Protein 1 Plays a Dominant Role in Glycogen Transport to Lysosomes in Liver*□S. Knock-out of an autophagy key gene Atg resulted in a decrease of glycogen content by 50 – 60% in skeletal muscles of GAA knock-out mice [12] This suggests that other routes exist for glycogen transport to lysosomes. The Stbd protein contains a putative N-terminal transmembrane region, an Atg interacting motif (AIM), and a C-terminal carbohydrate binding module family 20 (CBM20) [13,14,15] The observation that it binds to glycogen and interacts with the autophagy protein GABARAPL1 in cultured cells led to speculations that Stbd may function as a cargo-binding protein that delivers glycogen to lysosomes in a specific autophagic pathway [13, 14]. We generated Stbd1/GAA double knock-out (dKO) mice to explore the role of Stbd in glycogen transport to lysosomes, as accumulated lysosomal glycogen is an measurable indicator of glycogen transport to this organelle
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