N-Glycan-calnexin interactions in human factor VII secretion and deficiency

Wang, Hao; Wang, Lina; Li, Shuo; Dong, Ningzheng; Wu, Qingyu

doi:10.1016/j.biocel.2019.05.017

Cited by 8 publications

(3 citation statements)

References 46 publications

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“…N-glycosylation at this position seems to contribute little to the interaction with calnexin and the folding of the neighboring modules. In supporting of this hypothesis, studies in blood coagulation factor VII also show that abolishing N-glycosylation in the protease domain, but not between an epidermal growth factor-like and the protease domains, impaired factor VII folding and secretion ( 77 ). It is noteworthy that N-glycosylation site at N250 in human TMPRSS2 is conserved in all mammals, whereas the site at N286 is conserved only in primates ( Fig.…”

Section: Discussionmentioning

confidence: 98%

Transmembrane serine protease TMPRSS2 implicated in SARS-CoV-2 infection is autoactivated intracellularly and requires N-glycosylation for regulation

Zhang

Sun

et al. 2022

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 98%

Transmembrane serine protease TMPRSS2 implicated in SARS-CoV-2 infection is autoactivated intracellularly and requires N-glycosylation for regulation

Zhang

Sun

et al. 2022

Journal of Biological Chemistry

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“…Elimination of the N‐glycan–calnexin interaction inhibited hepsin folding and ER exiting. Previously, similar N‐glycan–calnexin‐mediated folding mechanisms were reported in other serine proteases, including corin, enteropeptidase, prothrombin, and clotting factor VII [60,61]. N‐glycosylation sites are common in the SRCR domains of cell surface receptors and ligand‐binding proteins.…”

Section: Hepsin Biosynthesis Activation and Sheddingmentioning

confidence: 65%

Hepsin: a multifunctional transmembrane serine protease in pathobiology

Wang

Sun

et al. 2020

The FEBS Journal

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Cell membrane-bound serine proteases are important in the maintenance of physiological homeostasis. Hepsin is a type II transmembrane serine protease highly expressed in the liver. Recent studies indicate that hepsin activates prohepatocyte growth factor in the liver to enhance Met signaling, thereby regulating glucose, lipid, and protein metabolism. In addition, hepsin functions in nonhepatic tissues, including the adipose tissue, kidney, and inner ear, to regulate adipocyte differentiation, urinary protein processing, and auditory function, respectively. In mouse models, hepsin deficiency lowers blood glucose, lipid, and protein levels, impairs uromodulin assembly in renal epithelial cells, and causes hearing loss. Elevated hepsin expression has also been found in many cancers. As a type II transmembrane protease, cell surface expression and zymogen activation are essential for hepsin activity. In this review, we discuss the current knowledge regarding hepsin biosynthesis, activation, and functions in pathobiology.

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“…3 Several N-glycosylation sites (N145, N322, and N360) were identified in FVII (factor VII), and mutation of these glycosylation sites inhibits FVII secretion and induces partial protein degradation. 54,55 Interestingly, the residue of N360 on FVII is glycosylated by the STT3B-MAGT1 complex. 18 However, in MAGT1-deficient blood plasma, normal levels of inactive and active forms of FVII were detected, indicating a compensatory mechanism, probably regulated by TUSC3.…”

Section: Discussionmentioning

confidence: 99%

MAGT1 Deficiency Dysregulates Platelet Cation Homeostasis and Accelerates Arterial Thrombosis and Ischemic Stroke in Mice

Gotru

Mammadova‐Bach

Sogkas

et al. 2023

ATVB

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BACKGROUND: MAGT1 (magnesium transporter 1) is a subunit of the oligosaccharide protein complex with thiol-disulfide oxidoreductase activity, supporting the process of N-glycosylation. MAGT1 deficiency was detected in human patients with X-linked immunodeficiency with magnesium defect syndrome and congenital disorders of glycosylation, resulting in decreased cation responses in lymphocytes, thereby inhibiting the immune response against viral infections. Curative hematopoietic stem cell transplantation of patients with X-linked immunodeficiency with magnesium defect causes fatal bleeding and thrombotic complications. METHODS: We studied the role of MAGT1 deficiency in platelet function in relation to arterial thrombosis and hemostasis using several in vitro experimental settings and in vivo models of arterial thrombosis and transient middle cerebral artery occlusion model of ischemic stroke. RESULTS: MAGT1-deficient mice ( Magt1 −/y ) displayed accelerated occlusive arterial thrombus formation in vivo, a shortened bleeding time, and profound brain damage upon focal cerebral ischemia. These defects resulted in increased calcium influx and enhanced second wave mediator release, which further reinforced platelet reactivity and aggregation responses. Supplementation of MgCl 2 or pharmacological blockade of TRPC6 (transient receptor potential cation channel, subfamily C, member 6) channels, but not inhibition of store-operated calcium entry, normalized the aggregation responses of Magt1 −/y platelets to the control level. GP (glycoprotein) VI activation of Magt1 −/y platelets resulted in hyperphosphorylation of Syk (spleen tyrosine kinase), LAT (linker for activation of T cells), and PLC (phospholipase C) γ2, whereas the inhibitory loop regulated by PKC (protein kinase C) was impaired. A hyperaggregation response to the GP VI agonist was confirmed in human platelets isolated from a MAGT1-deficient (X-linked immunodeficiency with magnesium defect) patient. Haploinsufficiency of TRPC6 in Magt1 −/y mice could normalize GP VI signaling, platelet aggregation, and thrombus formation in vivo. CONCLUSIONS: These results suggest that MAGT1 and TRPC6 are functionally linked. Therefore, deficiency or impaired functionality of MAGT1 could be a potential risk factor for arterial thrombosis and stroke.

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N-Glycan-calnexin interactions in human factor VII secretion and deficiency

Cited by 8 publications

References 46 publications

Transmembrane serine protease TMPRSS2 implicated in SARS-CoV-2 infection is autoactivated intracellularly and requires N-glycosylation for regulation

Transmembrane serine protease TMPRSS2 implicated in SARS-CoV-2 infection is autoactivated intracellularly and requires N-glycosylation for regulation

Hepsin: a multifunctional transmembrane serine protease in pathobiology

MAGT1 Deficiency Dysregulates Platelet Cation Homeostasis and Accelerates Arterial Thrombosis and Ischemic Stroke in Mice

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