Abstract:Glycosylation is a sophisticated informational system that controls specific biological functions at the cellular and organismal level. Dysregulation of glycosylation may underlie some of the most complex and common diseases of the modern era. In the past 5 years, microRNAs have come to the forefront as a critical regulator of the glycome. Herein, we review the current literature on miRNA regulation of glycosylation and how this work may point to a new way to identify the biological importance of glycosylation… Show more
“…In previous work we posited that miR regulation of a gene would predict the biological functions of that gene, a hypothesis we termed the miRNA Proxy Hypothesis 8,10,11 . Downregulation of B3GLCT activity has a known set of biological outcomes due to the existence of mutations in the gene in the human population, which cause a loss of activity.…”
Section: Mirs Downregulating B3glct Predict Peters' Plus Syndromementioning
confidence: 99%
“…To date, no study has comprehensively analyzed the human miRome regulation of a gene. miRs are emerging as critical regulators of the glycome [8][9][10][11] . Glycosylation is one of the most abundant and diverse posttranslational modifications with roles in almost every disease state 12 .…”
Section: Introductionmentioning
confidence: 99%
“…Thus, miRs can be used to identify (by proxy) the biological functions of specific glycosylation enzymes (or other proteins)." 8 We used this approach to identify glycosylation enzymes controlling cell cycle, providing additional evidence for our hypothesis 11 . Testing of this hypothesis and utilization of this approach to identify the biological functions of glycosylation enzymes requires a thorough knowledge of miR:target interactions.…”
MicroRNAs (miRNAs, miRs) finely tune protein expression and target networks of 100s-1000s of genes that control specific biological processes. They are critical regulators of glycosylation, one of the most diverse and abundant posttranslational modifications. In recent work, miRs have been shown to predict the biological functions of glycosylation enzymes, leading to the miRNA proxy hypothesis which states, if a miR drives a specific biological phenotype, the targets of that miR will drive the same biological phenotype. Testing of this powerful hypothesis is hampered by our lack of knowledge about miR targets. Target prediction suffers from low accuracy and a high false prediction rate. Herein, we develop a high-throughput experimental platform to analyze miR:target interactions, miRFluR. We utilize this system to analyze the interactions of the entire human miRome with beta-3-glucosyltransferase (B3GLCT), a glycosylation enzyme whose loss underpins the congenital disorder Peters Plus Syndrome. Although this enzyme is predicted by multiple algorithms to be highly targeted by miRs, we identify only 27 miRs that downregulate B3GLCT, a >96% false positive rate for prediction. Functional enrichment analysis of these validated miRs predict phenotypes associated with Peters Plus Syndrome, although B3GLCT is not in their known target network. Thus, biological phenotypes driven by B3GLCT may be driven by the target networks of miRs that regulate this enzyme, providing additional evidence for the miRNA Proxy Hypothesis.
“…In previous work we posited that miR regulation of a gene would predict the biological functions of that gene, a hypothesis we termed the miRNA Proxy Hypothesis 8,10,11 . Downregulation of B3GLCT activity has a known set of biological outcomes due to the existence of mutations in the gene in the human population, which cause a loss of activity.…”
Section: Mirs Downregulating B3glct Predict Peters' Plus Syndromementioning
confidence: 99%
“…To date, no study has comprehensively analyzed the human miRome regulation of a gene. miRs are emerging as critical regulators of the glycome [8][9][10][11] . Glycosylation is one of the most abundant and diverse posttranslational modifications with roles in almost every disease state 12 .…”
Section: Introductionmentioning
confidence: 99%
“…Thus, miRs can be used to identify (by proxy) the biological functions of specific glycosylation enzymes (or other proteins)." 8 We used this approach to identify glycosylation enzymes controlling cell cycle, providing additional evidence for our hypothesis 11 . Testing of this hypothesis and utilization of this approach to identify the biological functions of glycosylation enzymes requires a thorough knowledge of miR:target interactions.…”
MicroRNAs (miRNAs, miRs) finely tune protein expression and target networks of 100s-1000s of genes that control specific biological processes. They are critical regulators of glycosylation, one of the most diverse and abundant posttranslational modifications. In recent work, miRs have been shown to predict the biological functions of glycosylation enzymes, leading to the miRNA proxy hypothesis which states, if a miR drives a specific biological phenotype, the targets of that miR will drive the same biological phenotype. Testing of this powerful hypothesis is hampered by our lack of knowledge about miR targets. Target prediction suffers from low accuracy and a high false prediction rate. Herein, we develop a high-throughput experimental platform to analyze miR:target interactions, miRFluR. We utilize this system to analyze the interactions of the entire human miRome with beta-3-glucosyltransferase (B3GLCT), a glycosylation enzyme whose loss underpins the congenital disorder Peters Plus Syndrome. Although this enzyme is predicted by multiple algorithms to be highly targeted by miRs, we identify only 27 miRs that downregulate B3GLCT, a >96% false positive rate for prediction. Functional enrichment analysis of these validated miRs predict phenotypes associated with Peters Plus Syndrome, although B3GLCT is not in their known target network. Thus, biological phenotypes driven by B3GLCT may be driven by the target networks of miRs that regulate this enzyme, providing additional evidence for the miRNA Proxy Hypothesis.
“…2 ). Interested readers are encouraged to refer to two recent review papers on the other types of glycosylation [ 15 , 31 ]. Fig.…”
Section: Glycosylation Machinery and Its Regulatory Mechanism In Tumor Cellsmentioning
confidence: 99%
“…A key obstacle for miRNA therapeutics is the identification of ideal miRNA targets for different types of cancers. We still lack effective experimental methods for high throughput identification of miRNAs and their regulated genes [ 31 ]. Although many computational tools have been developed to identify miRNA target genes based on transcriptomic data in the past decades [ 69 ], these methods are beset with high false positive and false negative rates.…”
Section: Systems Glycobiology: Emerging Opportunities and Challenges For The Next Generation Of Cancer Immunotherapymentioning
Cancer immunotherapy has revolutionized treatment and led to an unprecedented wave of immuno-oncology research during the past two decades. In 2018, two pioneer immunotherapy innovators, Tasuku Honjo and James P. Allison, were awarded the Nobel Prize for their landmark cancer immunotherapy work regarding “cancer therapy by inhibition of negative immune regulation” –CTLA4 and PD-1 immune checkpoints. However, the challenge in the coming decade is to develop cancer immunotherapies that can more consistently treat various patients and cancer types. Overcoming this challenge requires a systemic understanding of the underlying interactions between immune cells, tumor cells, and immunotherapeutics. The role of aberrant glycosylation in this process, and how it influences tumor immunity and immunotherapy is beginning to emerge. Herein, we review current knowledge of miRNA-mediated regulatory mechanisms of glycosylation machinery, and how these carbohydrate moieties impact immune cell and tumor cell interactions. We discuss these insights in the context of clinical findings and provide an outlook on modulating the regulation of glycosylation to offer new therapeutic opportunities. Finally, in the coming age of systems glycobiology, we highlight how emerging technologies in systems glycobiology are enabling deeper insights into cancer immuno-oncology, helping identify novel drug targets and key biomarkers of cancer, and facilitating the rational design of glyco-immunotherapies. These hold great promise clinically in the immuno-oncology field.
The unfolded protein response (UPR) is a sensing and signaling pathway that surveys the endoplasmic reticulum (ER) for protein folding challenges and responds whenever issues are detected. UPR activation leads to upregulation of secretory pathway chaperones and quality control factors, as well as reduces the nascent protein load on the ER, thereby restoring and maintaining proteostasis. This paradigm‐defining view of the role of the UPR is accurate, but it elides additional key functions of the UPR in cell biology. In particular, recent work has revealed that the UPR can shape the structure and function of N‐ and O‐glycans installed on ER client proteins. This crosstalk between the UPR's reaction to protein misfolding and the regulation of glycosylation remains insufficiently understood. Still, emerging evidence makes it clear that the UPR, and particularly the IRE1‐XBP1s arm of the UPR, may be a central regulator of protein glycosylation, with important biological consequences. In this review, we discuss the crosstalk between proteostasis, the UPR, and glycosylation, present progress towards understanding biological functions of this crosstalk, and examine potential roles in diseases such as cancer.
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