More Than One Glycan Is Needed for ER Glucosidase II to Allow Entry of Glycoproteins into the Calnexin/Calreticulin Cycle

Deprez, Paola; Gautschi, Matthias; Helenius, Ari

doi:10.1016/j.molcel.2005.05.029

Cited by 127 publications

(142 citation statements)

References 42 publications

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“…Indeed, our experiments with control cells at low [Ca 2ϩ ] o also result in a reduced number of trichocysts. Theoretically a primary effect of interfering with Ca 2ϩ homeostasis by CRC-II-1 silencing could be the requirement of a Ca 2ϩ -activated calreticulin complex for correct processing and folding of secretory proteins (20,38). Although a calreticulinlike protein occurs in Paramecium (73), we see in Western blots, after CRC-II-1 silencing, a correctly cleaved TMP4 protein comparable to the size of processed TMPs in normal cells (31,99).…”

Section: Discussionmentioning

confidence: 86%

Novel Types of Ca²⁺ Release Channels Participate in the Secretory Cycle of Paramecium Cells

Ladenburger¹,

Sehring²,

Korn³

et al. 2009

Molecular and Cellular Biology

121

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A database search of the Paramecium genome reveals 34 genes related to Ca 2؉ -release channels of the inositol-1,4,5-trisphosphate (IP 3 ) or ryanodine receptor type (IP 3 R, RyR). Phylogenetic analyses show that these Ca 2؉ release channels (CRCs) can be subdivided into six groups (Paramecium tetraurelia CRC-I to CRC-VI), each one with features in part reminiscent of IP 3 Rs and RyRs. We characterize here the P. tetraurelia CRC-IV-1 gene family, whose relationship to IP 3 Rs and RyRs is restricted to their C-terminal channel domain. CRC-IV-1 channels localize to cortical Ca 2؉ stores (alveolar sacs) and also to the endoplasmic reticulum. This is in contrast to a recently described true IP 3 channel, a group II member (P. tetraurelia IP 3 R N -1), found associated with the contractile vacuole system. Silencing of either one of these CRCs results in reduced exocytosis of dense core vesicles (trichocysts), although for different reasons. Knockdown of P. tetraurelia IP 3 R N affects trichocyst biogenesis, while CRC-IV-1 channels are involved in signal transduction since silenced cells show an impaired release of Ca 2؉ from cortical stores in response to exocytotic stimuli. Our discovery of a range of CRCs in Paramecium indicates that protozoans already have evolved multiple ways for the use of Ca 2؉ as signaling molecule.Ca 2ϩ is an important component of cell activity in all organisms, from protozoa to mammals. Thereby Ca 2ϩ may originate from the outside medium and/or from internal stores (7, 18). Ca 2ϩ release from internal stores is mediated by various Ca 2ϩ release channels (CRCs), of which the inositol-1,4,5-trisphosphate receptor (IP 3 R) and ryanodine receptor (RyR) families have been studied most extensively (8,9,29,63 (14). IP 3 generates and maintains a Ca 2ϩ gradient in the hyphal tip of Neurospora crassa and the IP 3 -sensitive channels have been reconstituted and characterized with the planar bilayer method (87). In summary, these publications suggest that IP 3 -dependent signaling pathways are conserved among unicellular organisms, including protozoa.Despite these data, the molecular characterization of IP 3 or ryanodine receptors in low eukaryotes is currently a challenge since the identification of orthologues has not been possible thus far, probably because of evolutionary sequence divergence (66). Traynor et al. (96) identified an IP 3 receptor-like protein, IplA, in Dictyostelium discoideum, which possesses regions related to IP 3 R sequences, but thus far no evidence for IP 3 interaction exists. We have recently described an IP 3 R in the ciliated protozoa Paramecium tetraurelia (referred to here as P. tetraurelia IP 3 R N ) (53), with features characteristic of mammalian IP 3 Rs in terms of topology and ability for IP 3 binding. The expression level of P. tetraurelia IP 3 R N is modulated by extracellular Ca 2ϩ concentrations ([Ca 2ϩ ] o ) and immunofluorescence studies reveal an unexpected localization to the contractile vacuole complex (CVC), the major organelle involved in osmoregulation...

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Section: Discussionmentioning

confidence: 86%

Novel Types of Ca²⁺ Release Channels Participate in the Secretory Cycle of Paramecium Cells

Ladenburger¹,

Sehring²,

Korn³

et al. 2009

Molecular and Cellular Biology

121

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“…This may reflect a genuine difference in the binding affinity of calnexin for the different receptor forms, as it has been demonstrated earlier that the efficient binding of calnexin to glycoproteins takes place only if at least two core N-glycans are attached to the nascent protein (42,43).…”

Section: Discussionmentioning

confidence: 93%

N-Glycan-mediated Quality Control in the Endoplasmic Reticulum Is Required for the Expression of Correctly Folded δ-Opioid Receptors at the Cell Surface

Markkanen

Petäjä-Repo

2008

Journal of Biological Chemistry

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A great majority of G protein-coupled receptors are modified by N-glycosylation, but the functional significance of this modification for receptor folding and intracellular transport has remained elusive. Here we studied these phenomena by mutating the two N-terminal N-glycosylation sites (Asn 18 and Asn 33 ) of the human ␦-opioid receptor, and expressing the mutants from the same chromosomal integration site in stably transfected inducible HEK293 cells. Both N-glycosylation sites were used, and their abolishment decreased the steady-state level of receptors at the cell surface. However, pulse-chase labeling, cell surface biotinylation, and immunofluorescence microscopy revealed that this was not because of intracellular accumulation. Instead, the non-N-glycosylated receptors were exported from the endoplasmic reticulum with enhanced kinetics. The results also revealed differences in the significance of the individual N-glycans, as the one attached to Asn 33 was found to be more important for endoplasmic reticulum retention of the receptor. The non-N-glycosylated receptors did not show gross functional impairment, but flow cytometry revealed that a fraction of them was incapable of ligand binding at the cell surface. In addition, the receptors that were devoid of N-glycans showed accelerated turnover and internalization and were targeted for lysosomal degradation. The results accentuate the importance of protein conformation-based screening before export from the endoplasmic reticulum, and demonstrate how the system is compromised when N-glycosylation is disrupted. We conclude that N-glycosylation of the ␦-opioid receptor is needed to maintain the expression of fully functional and stable receptor molecules at the cell surface.

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“…N-Glycan multiplicity (NX(S/T) sites per glycoprotein) increases affinity for lectins with functional consequences, as reported for ER chaperones calnexin and calreticulin, and the galectins at the cell surface (12,43). To determine whether each of the five NX(S/T) sites in murine Gcgr are occupied by N-glycans, the sites were individually mutated from asparagine to glutamine.…”

Section: The Mgat5mentioning

confidence: 99%

N-Glycan Remodeling on Glucagon Receptor Is an Effector of Nutrient Sensing by the Hexosamine Biosynthesis Pathway

Johswich

Longuet

Pawling

et al. 2014

Journal of Biological Chemistry

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Background:The hexosamine biosynthesis pathway to UDP-GlcNAc has been implicated in glucose homeostasis. Results: UDP-GlcNAc and Golgi N-acetylglucosaminyltransferases modify the N-glycans on glucagon receptor, which increases sensitivity to glucagon in vivo. Conclusion: The hexosamine biosynthesis pathway contributes to glucose homeostasis, in part through N-glycan branching on glucagon receptor. Significance: Hepatic Mgat5 and the N-glycan branching pathway may be a therapeutic target for control of glycemia.

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More Than One Glycan Is Needed for ER Glucosidase II to Allow Entry of Glycoproteins into the Calnexin/Calreticulin Cycle

Cited by 127 publications

References 42 publications

Novel Types of Ca²⁺ Release Channels Participate in the Secretory Cycle of Paramecium Cells

Novel Types of Ca²⁺ Release Channels Participate in the Secretory Cycle of Paramecium Cells

N-Glycan-mediated Quality Control in the Endoplasmic Reticulum Is Required for the Expression of Correctly Folded δ-Opioid Receptors at the Cell Surface

N-Glycan Remodeling on Glucagon Receptor Is an Effector of Nutrient Sensing by the Hexosamine Biosynthesis Pathway

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More Than One Glycan Is Needed for ER Glucosidase II to Allow Entry of Glycoproteins into the Calnexin/Calreticulin Cycle

Cited by 127 publications

References 42 publications

Novel Types of Ca2+ Release Channels Participate in the Secretory Cycle of Paramecium Cells

Novel Types of Ca2+ Release Channels Participate in the Secretory Cycle of Paramecium Cells

N-Glycan-mediated Quality Control in the Endoplasmic Reticulum Is Required for the Expression of Correctly Folded δ-Opioid Receptors at the Cell Surface

N-Glycan Remodeling on Glucagon Receptor Is an Effector of Nutrient Sensing by the Hexosamine Biosynthesis Pathway

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Novel Types of Ca²⁺ Release Channels Participate in the Secretory Cycle of Paramecium Cells

Novel Types of Ca²⁺ Release Channels Participate in the Secretory Cycle of Paramecium Cells