The fibrinogen C-terminal domain is seldom C-mannosylated but its C-mannosylation is important for the secretion of microfibril-associated glycoprotein 4

Osada, Yoshiyuki; Suzuki, Takehiro; Mizuta, Hayato; Mori, Keisuke; Miura, Kazuki; Dohmae, Naoshi; Simizu, Siro

doi:10.1016/j.bbagen.2020.129637

Cited by 14 publications

(11 citation statements)

References 43 publications

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“…There are four homologs of DPY19 (DPY19L1-L4) in mammals, and it has been demonstrated that DPY19L1 and DPY19L3 have a C -mannosyltransferase activity [ 11 , 12 ]. It has been revealed that C -mannosylation involves protein secretion, intracellular localization, and protein folding, which are similar with other forms of glycosylation [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]; however, the role of C -mannosyltransferases on biological events is still obscured.…”

Section: Introductionmentioning

confidence: 99%

Involvement of DPY19L3 in Myogenic Differentiation of C2C12 Myoblasts

et al. 2021

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DPY19L3 has been identified as a C-mannosyltransferase for thrombospondin type-1 repeat domain-containing proteins. In this study, we focused on the role of DPY19L3 in the myogenic differentiation of C2C12 mouse myoblast cells. We carried out DPY19L3 gene depletion using the CRISPR/Cas9 system. The result showed that these DPY19L3-knockout cells could not be induced for differentiation. Moreover, the phosphorylation levels of MEK/ERK and p70S6K were suppressed in the DPY19L3-knockout cells compared with that of parent cells, suggesting that the protein(s) that is(are) DPY19L3-mediated C-mannosylated and regulate(s) MEK/ERK or p70S6K signaling is(are) required for the differentiation.

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Section: Introductionmentioning

confidence: 99%

Involvement of DPY19L3 in Myogenic Differentiation of C2C12 Myoblasts

et al. 2021

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“…C-mannosylation of VMO1 affects its stability but not secretion C-mannosylation also affects the secretion of its substrate proteins even if not belonging to proteins containing TSR1 domain and type I cytokine receptors [6,8,29]. To assess the effect of C-mannosylation on the secretion of VMO1, we established stable HT1080 cell lines overexpressing C-terminally Myc-his 6 -tagged wild-type form of VMO1 and a C-mannosylationdefective mutant form of VMO1, termed as HT1080-VMO1-MH and HT1080-VMO1/W105F-MH, respectively (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…C ‐mannosylation is important for the secretion, intracellular localization, and stability of proteins belonging to these two categories [ 3 ]. In general, C ‐mannosylation assists intracellular trafficking from ER to the Golgi apparatus and secretion of substrate proteins [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. C ‐mannosyltryptophan residues, forming the Trp‐Arg ladder in the TSR1 domain, support the folding process and enhance the stability of the folded UNC‐5 protein, a TSR1 domain‐containing netrin receptor [ 11 ].…”

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confidence: 99%

Destabilization of vitelline membrane outer layer protein 1 homolog (VMO1) by C‐mannosylation

et al. 2023

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C‐mannosylation is a rare type of protein glycosylation whereby a single mannose is added to the first tryptophan in the consensus sequence Trp‐Xaa‐Xaa‐Trp/Cys (in which Xaa represents any amino acid). Its consensus sequence is mainly found in proteins containing a thrombospondin type‐1 repeat (TSR1) domain and in type I cytokine receptors. In these proteins, C‐mannosylation affects protein secretion, intracellular localization, and protein stability; however, the role of C‐mannosylation in proteins that are not type I cytokine receptors and/or do not contain a TSR1 domain is less well explored. In this study, we focused on human vitelline membrane outer layer protein 1 homolog (VMO1). VMO1, which possesses two putative C‐mannosylation sites, is a 21‐kDa secreted protein that does not contain a TSR1 domain and is not a type I cytokine receptor. Mass spectrometry analyses revealed that VMO1 is C‐mannosylated at Trp105 but not at Trp44. Although C‐mannosylation does not affect the extracellular secretion of VMO1, it destabilizes the intracellular VMO1. In addition, a structural comparison between VMO1 and C‐mannosylated VMO1 showed that the modification of the mannose changes the conformation of three loops in VMO1. Taken together, our results demonstrate the first example of C‐mannosylation for protein destabilization of VMO1.

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“…The secretion levels of ADAMTS16 and UNC5A were reduced in C -mannosyltransferase-deficient cells, suggesting that secretion depends on C -mannosylation. In addition to UNC5A and ADAMTS16, C -mannosyltransferase-deficient cell lines and experimental substitution of Trp for non- C -mannosylated amino acids caused disturbance in the secretion of proteins, such as mucins (MUC5AC and MUC5B) [ 78 , 79 ], TSP-1 [ 50 ], mindin (Spondin2) [ 52 ], ADAMTSL1 [ 53 ], MIG-21 [ 54 ], ADAMTS13 [ 56 ], MIC2 [ 60 ], R-spondin1 [ 62 ], R-spondin3 [ 63 ], ADAMTS4 [ 67 ], Isthmin-1 [ 68 ], lipoprotein lipase [ 86 ], and microfibril-associated glycoprotein 4 (MFAP4) [ 87 ]. C -Mannosylation also regulated cell surface localization of IL-21R [ 71 ] and thrombopoietin receptor (TPOR) [ 72 ].…”

Section: Biochemical Aspects Of Protein C -Mannosylation and C -Man-trpmentioning

confidence: 99%

Protein C-Mannosylation and C-Mannosyl Tryptophan in Chemical Biology and Medicine

et al. 2021

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C-Mannosylation is a post-translational modification of proteins in the endoplasmic reticulum. Monomeric α-mannose is attached to specific Trp residues at the first Trp in the Trp-x-x-Trp/Cys (W-x-x-W/C) motif of substrate proteins, by the action of C-mannosyltransferases, DPY19-related gene products. The acceptor substrate proteins are included in the thrombospondin type I repeat (TSR) superfamily, cytokine receptor type I family, and others. Previous studies demonstrated that C-mannosylation plays critical roles in the folding, sorting, and/or secretion of substrate proteins. A C-mannosylation-defective gene mutation was identified in humans as the disease-associated variant affecting a C-mannosylation motif of W-x-x-W of ADAMTSL1, which suggests the involvement of defects in protein C-mannosylation in human diseases such as developmental glaucoma, myopia, and/or retinal defects. On the other hand, monomeric C-mannosyl Trp (C-Man-Trp), a deduced degradation product of C-mannosylated proteins, occurs in cells and extracellular fluids. Several studies showed that the level of C-Man-Trp is upregulated in blood of patients with renal dysfunction, suggesting that the metabolism of C-Man-Trp may be involved in human kidney diseases. Together, protein C-mannosylation is considered to play important roles in the biosynthesis and functions of substrate proteins, and the altered regulation of protein C-manosylation may be involved in the pathophysiology of human diseases. In this review, we consider the biochemical and biomedical knowledge of protein C-mannosylation and C-Man-Trp, and introduce recent studies concerning their significance in biology and medicine.

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The fibrinogen C-terminal domain is seldom C-mannosylated but its C-mannosylation is important for the secretion of microfibril-associated glycoprotein 4

Cited by 14 publications

References 43 publications

Involvement of DPY19L3 in Myogenic Differentiation of C2C12 Myoblasts

Involvement of DPY19L3 in Myogenic Differentiation of C2C12 Myoblasts

Destabilization of vitelline membrane outer layer protein 1 homolog (VMO1) by C‐mannosylation

Protein C-Mannosylation and C-Mannosyl Tryptophan in Chemical Biology and Medicine

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