Stbd1 is highly elevated in skeletal muscle of Pompe disease mice but suppression of its expression does not affect lysosomal glycogen accumulation

Yi, Haiqing; Fredrickson, Keri; DAS, S; Kishnani, Priya S.; Sun, Baodong

doi:10.1016/j.ymgme.2013.05.004

Cited by 20 publications

(21 citation statements)

References 19 publications

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“…This provoked a great expectation that Stbd1 might be a new therapeutic target for Pompe disease. Contradictorily, our previous study demonstrated that significant knockdown of Stbd1 in skeletal muscle of GAA knock-out mice did not reduce lysosomal glycogen accumulation, suggesting that Stbd1 may not be involved in lysosomal glycogen trafficking at least in this tissue (16). In an effort to clarify this controversy, we generated Stbd1/GAA double knock-out mice.…”

Section: Discussionmentioning

confidence: 94%

“…The observation that it binds to glycogen and interacts with the autophagy protein GABARAPL1 in cultured cells led to speculations that Stbd1 may function as a cargo-binding protein that delivers glycogen to lysosomes in a specific autophagic pathway (13,14). Contradictorily, our previous study undermined this proposition, as significant knockdown of Stbd1 in skeletal muscle of GAA knock-out (GKO) mice did not affect lysosomal glycogen storage in the tissue (16). In this study, we generated Stbd1/GAA double knock-out (dKO) mice to explore the role of Stbd1 in glycogen transport to lysosomes, as accumulated lysosomal glycogen is an easily measurable indicator of glycogen transport to this organelle.…”

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confidence: 92%

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Starch Binding Domain-containing Protein 1 Plays a Dominant Role in Glycogen Transport to Lysosomes in Liver

Sun¹,

Yi²,

Yang

et al. 2016

Journal of Biological Chemistry

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A small portion of cellular glycogen is transported to and degraded in lysosomes by acid ␣-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 knockout 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.Liver and muscle are the two primary sites for glycogen metabolism in mammals. Glycogen is synthesized and mostly degraded in the cytoplasm, but a small percentage of glycogen is transported into the lysosomes and hydrolyzed by the enzyme acid ␣-glucosidase (GAA) 3 (1-3). Deficiency of GAA causes Pompe disease (glycogen storage disease type II), resulting in a progressive lysosomal glycogen accumulation and dysfunction in cardiac and skeletal muscle and other tissues (4 -6). Enzyme replacement therapy with recombinant human GAA is the only available therapy for this disorder to have remarkable success, but it also has significant limitations such as high titer antibody formation and difficulties in delivering the therapeutic protein to skeletal muscle tissues (7-11). A conceivable alternative way to treat Pompe disease would be to block the transport of cytoplasmic glycogen to the lysosomes. Thus, understanding how glycogen enters the lysosome is a critical step in finding new therapeutic targets for Pompe disease. It has been demonstrated that conventional autophagy (macroautophagy) plays an important role in the transport of glycogen to lysosomes in skeletal muscle (12). Specifically, knock-out of an autophagy key gene Atg7 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. In recent studies, starch binding domain-containing protein 1 (Stbd1) has gained attention for its potential involvement in glycogen transport. The Stbd1 protein contains a putat...

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 92%

Starch Binding Domain-containing Protein 1 Plays a Dominant Role in Glycogen Transport to Lysosomes in Liver

Sun¹,

Yi²,

Yang

et al. 2016

Journal of Biological Chemistry

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“…This hypothesis was addressed by means of a Stbd1 knockdown approach in Gaa −/− mice. Despite a reduction in Stbd1 expression levels by 23–28% in skeletal and cardiac muscle, a decrease in the amount of accumulated glycogen in the affected tissues did not occur (Yi et al, 2013). However, a recent report showed that in Stbd1 / Gaa double knockout mice, glycogen storage is reduced in the liver but not muscle, supporting a role for Stbd1 in lysosomal glycogen transport in the liver (Sun et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Mouse Stbd1 is N-myristoylated and affects ER–mitochondria association and mitochondrial morphology

Demetriadou

Morales-Sanfrutos

Nearchou

et al. 2017

Journal of Cell Science

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Starch binding domain-containing protein 1 (Stbd1) is a carbohydrate-binding protein that has been proposed to be a selective autophagy receptor for glycogen. Here, we show that mouse Stbd1 is a transmembrane endoplasmic reticulum (ER)-resident protein with the capacity to induce the formation of organized ER structures in HeLa cells. In addition to bulk ER, Stbd1 was found to localize to mitochondria-associated membranes (MAMs), which represent regions of close apposition between the ER and mitochondria. We demonstrate that N-myristoylation and binding of Stbd1 to glycogen act as major determinants of its subcellular targeting. Moreover, overexpression of non-myristoylated Stbd1 enhanced the association between ER and mitochondria, and further induced prominent mitochondrial fragmentation and clustering. Conversely, shRNA-mediated Stbd1 silencing resulted in an increase in the spacing between ER and mitochondria, and an altered morphology of the mitochondrial network, suggesting elevated fusion and interconnectivity of mitochondria. Our data unravel the molecular mechanism underlying Stbd1 subcellular targeting, support and expand its proposed function as a selective autophagy receptor for glycogen and uncover a new role for the protein in the physical association between ER and mitochondria.

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“…In Pompe disease, glycogen abnormally accumulates due to a deficiency in the lysosomal enzyme, acid-α-glucosidase [10]. Interestingly, STBD1 levels are elevated in a mouse model of Pompe disease [11]. However, suppression of STBD1 levels did not affect lysosomal glycogen accumulation.…”

Section: Introductionmentioning

confidence: 99%

The carbohydrate-binding domain of overexpressed STBD1 is important for its stability and protein–protein interactions

et al. 2014

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STBD1 (starch-binding domain-containing protein 1) belongs to the CBM20 (family 20 carbohydrate binding module) group of proteins, and is implicated in glycogen metabolism and autophagy. However, very little is known about its regulation or interacting partners. Here, we show that the CBM20 of STBD1 is crucial for its stability and ability to interact with glycogen-associated proteins. Mutation of a conserved tryptophan residue (W293) in this domain abolished the ability of STBD1 to bind to the carbohydrate amylose. Compared with the WT (wild-type) protein, this mutant exhibited rapid degradation that was rescued upon inhibition of the proteasome. Furthermore, STBD1 undergoes ubiquitination when expressed in COS cells, and requires the N-terminus for this process. In contrast, inhibition of autophagy did not significantly affect protein stability. In overexpression experiments, we discovered that STBD1 interacts with several glycogen-associated proteins, such as GS (glycogen synthase), GDE (glycogen debranching enzyme) and Laforin. Importantly, the W293 mutant of STBD1 was unable to do so, suggesting an additional role for the CBM20 domain in protein–protein interactions. In HepG2 hepatoma cells, overexpressed STBD1 could associate with endogenous GS. This binding increased during glycogenolysis, suggesting that glycogen is not required to bridge this interaction. Taken together, our results have uncovered new insights into the regulation and binding partners of STBD1.

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Stbd1 is highly elevated in skeletal muscle of Pompe disease mice but suppression of its expression does not affect lysosomal glycogen accumulation

Abstract: role in intracellular glycogen trafficking into lysosomes. We report here that Stbd1 expression is markedly

Cited by 20 publications

References 19 publications

Starch Binding Domain-containing Protein 1 Plays a Dominant Role in Glycogen Transport to Lysosomes in Liver

Starch Binding Domain-containing Protein 1 Plays a Dominant Role in Glycogen Transport to Lysosomes in Liver

Mouse Stbd1 is N-myristoylated and affects ER–mitochondria association and mitochondrial morphology

The carbohydrate-binding domain of overexpressed STBD1 is important for its stability and protein–protein interactions

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