Mannose-6-phosphate regulates destruction of lipid-linked oligosaccharides

Gao, Ningguo; Shang, Jie; Huynh, Dang; Manthati, Vijaya L.; Arias, Carolina; Harding, Heather P.; Kaufman, Randal J.; Mohr, Ian; Ron, David; Falck, John R.; Lehrman, Mark A.

doi:10.1091/mbc.e11-04-0286

Cited by 30 publications

(38 citation statements)

References 69 publications

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“…There are well-established connections between stress response and protein-and lipid-linked oligosaccharide metabolism (71,129). Stress-and nutrient-dependent changes in oligosaccharide levels can trigger the UPR (83)(84)(85)(86).…”

Section: Discussionmentioning

confidence: 99%

Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Adhikari

Vadaie

Chow

et al. 2015

Molecular and Cellular Biology

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bSignaling mucins are evolutionarily conserved regulators of signal transduction pathways. The signaling mucin Msb2p regulates the Cdc42p-dependent mitogen-activated protein kinase (MAPK) pathway that controls filamentous growth in yeast. The cleavage and release of the glycosylated inhibitory domain of Msb2p is required for MAPK activation. We show here that proteolytic processing of Msb2p was induced by underglycosylation of its extracellular domain. Cleavage of underglycosylated Msb2p required the unfolded protein response (UPR), a quality control (QC) pathway that operates in the endoplasmic reticulum (ER). The UPR regulator Ire1p, which detects misfolded/underglycosylated proteins in the ER, controlled Msb2p cleavage by regulating transcriptional induction of Yps1p, the major protease that processes Msb2p. Accordingly, the UPR was required for differentiation to the filamentous cell type. Cleavage of Msb2p occurred in conditional trafficking mutants that trap secretory cargo in the endomembrane system. Processed Msb2p was delivered to the plasma membrane, and its turnover by the ubiquitin ligase Rsp5p and ESCRT attenuated the filamentous-growth pathway. We speculate that the QC pathways broadly regulate signaling glycoproteins and their cognate pathways by recognizing altered glycosylation patterns that can occur in response to extrinsic cues. Signaling mucins are evolutionarily conserved regulators of signal transduction pathways (1-4). Signaling mucins are composed of a highly glycosylated extracellular domain that contains a mucin homology domain (MHD), which is defined by tandem repeats rich in Ser/Thr/Pro residues. The extracellular domain is connected by a single-pass transmembrane (TM) alpha helix to a cytosolic signaling domain, which associates with a diverse array of proteins that regulate mitogen-activated protein kinase (MAPK) pathways, Akt, ␤-catenin, and other pathways (5-8). Signaling mucins are overexpressed in different cancers, where they contribute to cell proliferation and metastasis (6). They are diagnostic biomarkers for cancers (9) and targets for immunotherapies (10,11). Therefore, the mechanisms by which signaling mucins and related glycoproteins are regulated is of intense interest.In the budding yeast Saccharomyces cerevisiae, the mucin-like glycoprotein Msb2p regulates the MAPK pathway that controls filamentous growth, a cell differentiation behavior that occurs in response to nutrient limitation (12-14). The extracellular domain of Msb2p is extensively glycosylated. Msb2p is modified by Nlinked and O-linked glycosylation and contains a canonical MHD that is itself highly glycosylated (15, 16). In a landmark study, Yang et al. identified Pmt4p as the major O-mannosyltransferase for Msb2p (17). Pmt4p is a member of an evolutionarily conserved protein mannosyl transferase (Pmt) gene family (2, 18). Msb2p also contains a cytosolic signaling domain. The cytosolic domain of Msb2p associates with the Rho GTPase Cdc42p (15), which is a ubiquitous regulator of cell polarity and signaling...

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Section: Discussionmentioning

confidence: 99%

Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Adhikari

Vadaie

Chow

et al. 2015

Molecular and Cellular Biology

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“…This important method demonstrated that when lightly permeabilized fibroblasts are incubated with 50 μM Man-6-P, comparable to its normal intracellular level, it specifically cleaves only mature LLO, releasing Glc 3 Man 9 GlcNAc 2 [41,42]. This effect was highly specific for Man-6-P and has been confirmed in another study, however, it failed to show any decrease in N-glycosylation [43].…”

Section: Mannose Metabolism In Cellsmentioning

confidence: 95%

Mannose metabolism: More than meets the eye

Sharma

Ichikawa

Freeze

2014

Biochemical and Biophysical Research Communications

176

168

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Mannose is a simple sugar with a complex life. It’s a welcome therapy for genetic and acquired human diseases, but it kills honeybees and blinds baby mice. It could cause diabetic complications. Mannose chemistry, metabolism, and metabolomics in cells, tissues and mammals can help explain these multiple systemic effects. Mannose has good, bad or ugly outcomes depending on its steady state levels and metabolic flux. This review describes the role of mannose at cellular level and its impact on organisms.

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“…A curious aspect is that pmm2 morphants have increased amounts of Man-6-P. The accumulation correlates with the loss of LLO and appearance of free oligosaccharides, presumably released from the LLO (45,46). These results recall important in vitro studies showing that increased Man-6-P levels lead to degradation of mature LLO precursor and release of the intact glycan.…”

Section: Rediscovering Sugar Metabolismmentioning

confidence: 66%

“…Intracellular accumulation of various sugar phosphates or other metabolic byproducts appears to prevent full N-glycosylation in selected cells and tissues. Only Man-6-P has been shown to have an effect on LLO levels (45). It is clear that mutations in fundamental glucose utilization pathways must now consider additional cell-specific effects on glycosylation.…”

Section: Rediscovering Sugar Metabolismmentioning

confidence: 99%

Understanding Human Glycosylation Disorders: Biochemistry Leads the Charge

Freeze

2013

Journal of Biological Chemistry

194

141

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Nearly 70 inherited human glycosylation disorders span a breathtaking clinical spectrum, impacting nearly every organ system and launching a family-driven diagnostic odyssey. Advances in genetics, especially next generation sequencing, propelled discovery of many glycosylation disorders in single and multiple pathways. Interpretation of whole exome sequencing results, insights into pathological mechanisms, and possible therapies will hinge on biochemical analysis of patient-derived materials and animal models. Biochemical diagnostic markers and readouts offer a physiological context to confirm candidate genes. Recent discoveries suggest novel perspectives for textbook biochemistry and novel research opportunities. Basic science and patients are the immediate beneficiaries of this bidirectional collaboration.

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Mannose-6-phosphate regulates destruction of lipid-linked oligosaccharides

Cited by 30 publications

References 69 publications

Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Mannose metabolism: More than meets the eye

Understanding Human Glycosylation Disorders: Biochemistry Leads the Charge

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