Subcellular Localization and Physiological Significance of Intracellular Mannan-binding Protein

Abstract

Mannan-binding protein (MBP) is a C-type mammalian lectin specific for mannose and N-acetylglucosamine. MBP is mainly synthesized in the liver and occurs naturally in two forms, serum MBP (S-MBP) and intracellular MBP (I-MBP). S-MBP activates complement in association with MBP-associated serine proteases via the lectin pathway. Despite our previous study (Mori, K., Kawasaki, T., and Yamashina, I. (1984) Arch. Biochem. Biophys. 232, 223-233), the subcellular localization of I-MBP and its functional implication have not been clarified yet. Here, as an extension of our previous studies, we have demonstrated that the expression of human MBP cDNA reproduces native MBP differentiation of S-MBP and I-MBP in human hepatoma cells. I-MBP shows distinct accumulation in cytoplasmic granules, and is predominantly localized in the endoplasmic reticulum (ER) and involved in COPII vesicle-mediated ER-to-Golgi transport. However, the subcellular localization of either a mutant (C236S/C244S) I-MBP, which lacks carbohydrate-binding activity, or the wild-type I-MBP in tunicamycin-treated cells shows an equally diffuse cytoplasmic distribution, suggesting that the unique accumulation of I-MBP in the ER and COPII vesicles is mediated by an N-glycan-lectin interaction. Furthermore, the binding of I-MBP with glycoprotein intermediates occurs in the ER, which is carbohydrate- and pH-dependent, and is affected by glucose-trimmed high-mannose-type oligosaccharides. These results strongly indicate that I-MBP may function as a cargo transport lectin facilitating ER-to-Golgi traffic in glycoprotein quality control. Mannan-binding protein (MBP) is a C-type mammalian lectin specific for mannose and N-acetylglucosamine. MBP is mainly synthesized in the liver and occurs naturally in two forms, serum MBP (S-MBP) and intracellular MBP (I-MBP). S-MBP activates complement in association with MBP-associated serine proteases via the lectin pathway. Despite our previous study (Mori, K., Kawasaki, T., and Yamashina, I. (1984) Arch. Biochem. Biophys. 232, 223-233), the subcellular localization of I-MBP and its functional implication have not been clarified yet. Here, as an extension of our previous studies, we have demonstrated that the expression of human MBP cDNA reproduces native MBP differentiation of S-MBP and I-MBP in human hepatoma cells. I-MBP shows distinct accumulation in cytoplasmic granules, and is predominantly localized in the endoplasmic reticulum (ER) and involved in COPII vesicle-mediated ER-to-Golgi transport. However, the subcellular localization of either a mutant (C236S/C244S) I-MBP, which lacks carbohydrate-binding activity, or the wild-type I-MBP in tunicamycin-treated cells shows an equally diffuse cytoplasmic distribution, suggesting that the unique accumulation of I-MBP in the ER and COPII vesicles is mediated by an N-glycan-lectin interaction. Furthermore, the binding of I-MBP with glycoprotein intermediates occurs in the ER, which is carbohydrate- and pH-dependent, and is affected by glucose-trimmed high-mannose-type oligosaccharides. These results strongly indicate that I-MBP may function as a cargo transport lectin facilitating ER-to-Golgi traffic in glycoprotein quality control. Mannan-binding protein (MBP), 4The abbreviations used are: MBP, mannan-binding protein; I-MBP, intracellular mannan-binding protein; S-MBP, serum mannan-binding protein; CRD, carbohydrate recognition domain; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum-Golgi intermediate compartment; COP, coatomer protein; LAMP-1, lysosome-associated membrane protein; DSP, dithiobis(succinimidylpropionate); SPR, surface plasmon resonance; HIV, human immunodeficiency virus; GFP, green fluorescent protein; pAb, polyclonal antibody; mAb, monoclonal antibody; CST, castanospermine; DMJ, deoxymannojirimycin; TM, tunicamycin; MEM, minimal essential medium; RFP, red fluorescent protein; GFP, green fluorescent protein; BiP, immunoglobulin-binding protein; PDI, protein disulfide isomerase. also known as mannan-binding lectin, is a Ca2+-dependent (C-type) mammalian lectin exhibiting primary specificity for mannose, fucose, and N-acetylglucosamine (1Kawasaki N. Kawasaki T. Yamashina I. J. Biochem.(Tokyo). 1983; 94: 937-947Crossref PubMed Scopus (220) Google Scholar). Because its discovery as a vital serum component associated with innate immunity, this lectin has been regarded as a multifunctional protein. MBP occurs naturally in two forms, secretory serum MBP (S-MBP) and intracellular MBP, which is termed I-MBP in this study and was called liver MBP (L-MBP) in our previous studies (2Mori K. Kawasaki T. Yamashina I. Arch. Biochem. Biophys. 1984; 232: 223-233Crossref PubMed Scopus (26) Google Scholar, 3Mori K. Kawasaki T. Yamashina I. Arch. Biochem. Biophys. 1988; 264: 647-656Crossref PubMed Scopus (17) Google Scholar, 4Ma Y. Shida H. Kawasaki T. J. Biochem. (Tokyo). 1997; 122: 810-818Crossref PubMed Scopus (37) Google Scholar). Human S-MBP and I-MBP are mainly synthesized in the liver and translated from a single form of mRNA. Both S-MBP and I-MBP are homooligomers composed of 32-kDa subunits. Each subunit has an NH2-terminal region containing cysteines involved in interchain disulfide bond formation, a collagen-like domain containing hydroxyproline and hydroxylysine residues, and a carbohydrate-recognition domain (CRD) with an amino acid sequence highly homologous to those of other C-type lectins (5Drickamer K. Dordal M.S. Reynolds L. J. Biol. Chem. 1986; 261: 6878-6887Abstract Full Text PDF PubMed Google Scholar). The CRD is specific for high-mannose oligosaccharide structures on exogenous and endogenous ligands, whereas the collagen-like domain is believed to be responsible for interactions with other effector proteins involved in host defense. S-MBP activates complement through interaction with three novel MBP-associated serine proteases, which is called the lectin pathway (6Fujita H. Nat. Rev. Immunol. 2002; 2: 346-353Crossref PubMed Scopus (569) Google Scholar). Furthermore, S-MBP was shown to exhibit novel cytotoxic activity toward some in vivo colorectal carcinoma cell experiments, which we proposed to term MBP-dependent cell-mediated cytotoxicity (4Ma Y. Shida H. Kawasaki T. J. Biochem. (Tokyo). 1997; 122: 810-818Crossref PubMed Scopus (37) Google Scholar, 7Ma Y. Uemura K. Oka S. Kozutsumi Y. Kawasaki N. Kawasaki T. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 371-375Crossref PubMed Scopus (124) Google Scholar). However, little is known about the subcellular localization and physiological significance of I-MBP. Recently, the functions of glycoprotein glycan chains in protein quality control have been attracting more attention, high-mannose-type oligosaccharides especially having been shown to play important roles in this process (8Sitia R. Braakman I. Nature. 2003; 426: 891-894Crossref PubMed Scopus (575) Google Scholar, 9Helenius A. Aebi M. Annu. Rev. Biochem. 2004; 73: 1019-1049Crossref PubMed Scopus (1620) Google Scholar). Glycosylation with an asparagine-linked (N-linked) oligosaccharides is a co-translational process that occurs in the ER. High-mannose-type oligosaccharides, presumably representing nascent core-glycosylated proteins, are subsequently transferred to the Golgi apparatus, where multiple processing reactions occur to produce more differentiated oligosaccharides, i.e. complex-type and hybrid-type oligosaccharides, by to the i.e. and the H. PubMed Scopus Google Scholar). synthesized secretory a of that results in quality and the secretory pathway A. Aebi M. Annu. Rev. Biochem. 2004; 73: 1019-1049Crossref PubMed Scopus (1620) Google Scholar). intracellular proteins, as and are involved in glycoprotein quality cargo and proteins and and L. A. Nat. Rev. Biol. 2003; PubMed Scopus Google Scholar). of are to high-mannose-type to I-MBP with the have to be to I-MBP is also involved in glycoprotein quality control. previous studies, we and MBP from liver and primary by and that the carbohydrate of high-mannose-type oligosaccharides, and K. Kawasaki T. Yamashina I. Arch. Biochem. Biophys. 1988; 264: 647-656Crossref PubMed Scopus (17) Google Scholar). we that the function of I-MBP may be associated with the intracellular transport of and quality control in the ER. this we have demonstrated that the expression of human MBP cDNA reproduces the native MBP differentiation of S-MBP and I-MBP on the in human hepatoma cell and have also that I-MBP predominantly as structures in the ER and ER-to-Golgi COPII this unique localization to on the carbohydrate binding activity of the lectin and also on the of endogenous carbohydrate in the ER we have the interaction of I-MBP with processing high-mannose-type oligosaccharides on a lysosome-associated membrane protein in the ER and on human immunodeficiency protein in the These results that I-MBP, as a cargo transport intracellular lectin, is associated with the intracellular transport and of some through processing high-mannose-type oligosaccharides on monoclonal LAMP-1, and from polyclonal specific for and green fluorescent protein from and polyclonal specific for from monoclonal protein disulfide and from and was by of and from and and from K. Y. I. H. Y. Chem. PubMed Scopus Google Scholar). was from i.e. and from and from and the from and from was from for and by and and of protein and wild-type and human with red fluorescent protein and green fluorescent protein from The or MBP is on the NH2-terminal of the fluorescent protein. was on by to the The MBP with a cytoplasmic CRD was to in and is termed in this lacks carbohydrate binding which results in of lectin and with hepatoma cell and and human and cell and in with serum and cells the wild-type and mutant (C236S/C244S) proteins, and and proteins in the of of shows a of the carbohydrate processing pathway in the ER and the specific of of the used in this carbohydrate processing used as T. R. A. Biochem. Biophys. 2004; PubMed Scopus Google and and with the for to the cells in the of for the to for and on the subcellular localization of the wild-type and and the interaction of with in the proteins the wild-type or mutant (C236S/C244S) MBP and protein the and with The cells subsequently and by the cells with proteins by The cells by for the and as A. H. T. N. K. Y. PubMed Scopus Google with a cells in and in for cells for with polyclonal by with with in J. PubMed Scopus Google and a of cells the wild-type and mutant (C236S/C244S) by to the the cells in two in of and and by in a by through a to about cells. and cells by for The was for The was in of The was the of a for and proteins by by with specific monoclonal the membrane and of the ER and the ER and Golgi of the wild-type and mutant and with to proteins from the by The and by with with and and for with for on a The was by the cells with in the by two in the and of cells wild-type or mutant (C236S/C244S) and wild-type and mutant (C236S/C244S) cells for in and to was with and to which and been experiments, cells for The was by of the and and with MEM, by a of in the of and The was and and the cells with and with and and from the and cells with and The proteins on a by to a the membrane with a or and the of of and LAMP-1, was from cells with MBP or in the of The proteins by in and on a by to a The membrane was with primary BiP, MBP, or by and by the with a of and binding for MBP was (4Ma Y. Shida H. Kawasaki T. J. Biochem. (Tokyo). 1997; 122: 810-818Crossref PubMed Scopus (37) Google Scholar). binding containing a wild-type or mutant of cells was with in the of for the proteins and with containing The proteins on a or and by with on MBP and or was with a and on a by the to the and with a of for the association and in and by the The interaction was as the in the The association and and from the association and in the by of the primary The was from the of the two NH2-terminal wild-type and mutant (C236S/C244S) in cells by on a as (4Ma Y. Shida H. Kawasaki T. J. Biochem. (Tokyo). 1997; 122: 810-818Crossref PubMed Scopus (37) Google Scholar). The NH2-terminal amino acid of the by of I-MBP in the the subcellular localization of I-MBP, we human MBP in human hepatoma cells. The equally diffuse cytoplasmic and cells not distinct accumulation in cytoplasmic granules, and a of structures structures be a are in the The two subcellular in the region are the ER and Golgi the subcellular of I-MBP multiple of I-MBP and or protein a of of two proteins in the ER and a in the Golgi However, I-MBP accumulation not to be with and not the of I-MBP, of of cells was of be the ER and ERGIC, and the Golgi with expression and is in the ER with expression the in the with the results the I-MBP is in the ER, in the and and not in the I-MBP ER and ER-to-Golgi we to the functional significance of I-MBP predominantly localized in the ER. Because ER-to-Golgi traffic vesicles and traffic vesicles are two transport vesicles the was that I-MBP was localized to two and associated with ER-to-Golgi transport. to that I-MBP be associated with ER-to-Golgi transport of via and traffic we I-MBP with proteins to more and the accumulation of I-MBP in shown in and the subcellular localization of I-MBP a of in COPII and in transport the of as structures the ER more diffuse of I-MBP also was in the ER ER are by the of COPII COPII as and are of structures Biol. PubMed Scopus Google Scholar). shown in and of I-MBP with that the with results that I-MBP ER and ER-to-Golgi COPII suggesting that may be associated with ER-to-Golgi transport of via with to the subcellular localization of I-MBP is to that I-MBP may as a cargo transport lectin for the of intermediates of some with high-mannose-type oligosaccharides from the ER-to-Golgi Recently, an to the endogenous the cargo recognition of MBP from through and in the of membrane Y. Kawasaki, M. Kawasaki, and T. Kawasaki, which is with oligosaccharides. LAMP-1, as a cargo recognition component of I-MBP, is in we the interaction of the I-MBP with the endogenous cells. shown in and in demonstrated the of an in the suggesting the interaction of I-MBP with in the subcellular which is known as a that with to and in the ER, was in the The of multiple of association and and and and with which are in the of proteins A. Y. Nat. Biol. 2: PubMed Scopus Google Scholar). These results that I-MBP a specific interaction with synthesized in the in the ER. is the that a in the ER-to-Golgi transport of mediated by I-MBP. of and on the is known that C-type lectin I-MBP for carbohydrate and the ER has a we the binding of I-MBP to in the ER is cells in the or of the ER shown in the suggesting that the binding of I-MBP with the glycoprotein intermediates in the ER is Ca2+-dependent and is mediated by the carbohydrate binding activity of I-MBP. to the roles of and mannose in the physiological interaction I-MBP and by TM, CST, or shown in cells with TM, the not be that with I-MBP. the cells with CST, the the of the suggesting that in the interaction may not be essential and that the of However, the cells with the mannose DMJ, the of the suggesting that binding to high-mannose-type oligosaccharides is more that to high-mannose-type oligosaccharides, and that the mannose are in cargo that the binding of I-MBP with LAMP-1, as of the intermediates of that occurs in the ER is carbohydrate- and and is also affected by and of the in the not be that the binding of I-MBP to a glycoprotein is mediated by on a we human hepatoma cells with which that the subcellular localization of I-MBP an equally diffuse cytoplasmic in to the structures in the control cells These results that the unique accumulation of I-MBP in the ER and COPII may be mediated by an N-glycan-lectin interaction. of I-MBP for and the of the an is that the I-MBP and predominantly localized in and COPII vesicles through recognition of by the CRD may function as a cargo transport lectin for in ER-to-Golgi the lectin activity of I-MBP is associated with its unique localization and the of we a mutant MBP with a cytoplasmic CRD, which the of in as shown in The two disulfide the in the of the CRD are for the binding The mutant (C236S/C244S) I-MBP lacks the carbohydrate-recognition and binding of MBP to However, is in the of the intracellular wild-type and mutant (C236S/C244S) Furthermore, the NH2-terminal amino acid of with a protein and the wild-type and mutant (C236S/C244S) the the amino of the and the amino of the form suggesting that the of multiple for as shown in the subcellular localization of the mutant (C236S/C244S) I-MBP on was an equally diffuse cytoplasmic the unique accumulation of the wild-type I-MBP the as that in the of tunicamycin-treated cells of the mutant (C236S/C244S) I-MBP with or proteins a of of the mutant MBP in the ER, not in the Golgi or the and COPII transport vesicles that a CRD is for the native subcellular localization of of the lectin activity of I-MBP for its functional and of the subcellular localization of the mutant (C236S/C244S) I-MBP in the ER and Golgi and of the functional of the mutant (C236S/C244S) I-MBP with the transport cells with the MBP with an ER a Golgi a or a COPII by the with The and of Human and in Human to the and differentiation of the wild-type and mutant (C236S/C244S) a was cells that the human wild-type and mutant (C236S/C244S) proteins, shown in the wild-type and mutant (C236S/C244S) proteins a a of a of the and and in the of the The wild-type lectin in the (S-MBP) and and of the was and of the be that other secretory proteins with of N. M. Nature. 1983; PubMed Scopus Google Scholar). These that I-MBP, which is predominantly localized in the ER and ER-to-Golgi COPII is not a of S-MBP, is a protein of functional significance in is in with our previous that the of I-MBP in liver is i.e. that of proteins, S. K. Kawasaki T. Yamashina I. Arch. Biochem. Biophys. 1988; PubMed Scopus Google Scholar). the of multiple and of the MBP the to complement and to be the to S-MBP, whereas the other the to function as a cargo transport lectin, in subcellular to I-MBP. The nascent S-MBP and I-MBP are to from hepatoma cells and localization in subcellular in to the wild-type MBP, the mutant (C236S/C244S) lectin in the (S-MBP) and of the was and of the of the mutant (C236S/C244S) I-MBP not to be by hepatoma cells. These results that I-MBP is not a of S-MBP and that an CRD is for the functional subcellular localization of I-MBP. of I-MBP, as by the that the mutant (C236S/C244S) I-MBP not from the ER, we used to the ER and Golgi shown in and the wild-type and mutant (C236S/C244S) with ER proteins and The wild-type I-MBP has also with the Golgi protein in with the However, the mutant (C236S/C244S) I-MBP was the ER. to the of I-MBP in the ER, we ER and the ER membrane and and used as for ER and The of the wild-type and mutant (C236S/C244S) was in the ER with a of the wild-type I-MBP in the Golgi not that I-MBP is a the results indicate that I-MBP is predominantly localized in the ER and in the and Golgi which is with the results of and suggesting that I-MBP is associated with the transport and of through its lectin and of of I-MBP in the of I-MBP in via oligosaccharides, we a for the association and of I-MBP with high-mannose oligosaccharides of shows a of the of oligosaccharides in the ER, and the in the ER and the interaction by and on a The binding of MBP in the to an and a control was as is from the ER through the Golgi to the to by Rev. 2003; PubMed Scopus Google Scholar). The of the ER and have been to be and and the in the to be Rev. 2003; PubMed Scopus Google Scholar, M. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). shown in the from the for The three in and the association and for the binding of MBP with oligosaccharides, i.e. and MBP more strongly with the binding with and Furthermore, the also that MBP and which is to the in the ER, of which is to the in the These that the association and of I-MBP with oligosaccharides of may be by the in and I-MBP may to oligosaccharide in the ER with and in the or Golgi with or These are with the results of our previous binding studies as a for is the is in the of to and the more and is Y. Kozutsumi Y. Kawasaki T. Yamashina I. J. Biol. Chem. Full Text PDF Google Scholar). The of binding in the ER and acid of the in the Golgi may the association and of I-MBP as a novel intracellular cargo of I-MBP with and of the of studies have shown that serum MBP to M. H. Y. J. 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Biol. 2003; PubMed Scopus Google to I-MBP with the subcellular interaction of I-MBP with may or formation, in and in However, studies are to the in vivo of I-MBP to transport of specific cargo and of MBP occurs naturally in two forms, S-MBP and I-MBP, which are synthesized mainly in the liver and translated from a single form of mRNA. S-MBP activates complement via the lectin pathway. However, subcellular localization and physiological function of I-MBP have been the we have demonstrated that the expression of human MBP cDNA reproduces the native MBP differentiation and of S-MBP and I-MBP in human hepatoma cell and I-MBP was to as a cargo intracellular lectin for glycoprotein transport the ER and Golgi synthesized in the ER and to and the ER in transport vesicles to the Golgi The transport and are by as of cargo proteins, the Golgi J. L. R. Annu. Rev. 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Here, as an extension of that we have the subcellular localization of I-MBP predominantly in the ER and ER-to-Golgi COPII and have the interaction of I-MBP with the processing high-mannose-type oligosaccharides on as an endogenous glycoprotein in the ER and protein as an exogenous suggesting its function as a novel cargo transport lectin for to that of cargo transport as and These are with our previous that the intracellular of I-MBP of oligosaccharides, and and or hybrid-type or complex-type oligosaccharides with or acid and the carbohydrate of intracellular mainly composed of intermediates of with of an of K. Kawasaki T. Yamashina I. Arch. Biochem. Biophys. 1988; 264: 647-656Crossref PubMed Scopus (17) Google Scholar). The protein transport and is of the in the study of protein traffic the involved as some of the important to the and of via interactions with a of intracellular lectins A. Aebi M. Annu. Rev. Biochem. 2004; 73: 1019-1049Crossref PubMed Scopus (1620) Google Scholar, L. A. Nat. Rev. Biol. 2003; PubMed Scopus Google Scholar, A. Aebi M. PubMed Scopus Google Scholar). The processing of oligosaccharides is in the ER by of the from the oligosaccharide is subsequently in the ER and in the Golgi through a of to the and extension of the oligosaccharides by Golgi to produce more differentiated oligosaccharides, i.e. complex-type and hybrid-type oligosaccharides, by to the i.e. and the A. Aebi M. Annu. Rev. Biochem. 2004; 73: 1019-1049Crossref PubMed Scopus (1620) Google Scholar). The in this study strongly indicate that I-MBP is an component of ER and COPII and that I-MBP a lectin domain that to a synthesized form of and with high-mannose-type and as a cargo transport The of I-MBP ER is not yet. However, that the mutant (C236S/C244S) I-MBP to the ER to our that I-MBP may function as a transport lectin for some cargo I-MBP and cargo binding occurs in the ER, and is to or to this I-MBP its lectin Both the ER and ER membrane are with or secretory be from ER and transport play an essential in the quality of this transport with specific secretory in the and transport These or with the proteins that form transport vesicles and as the to cargo M. Biochem. Sci. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). not to on I-MBP for is that other lectins that also glycoprotein transport. transport lectins have been The of mannose lectins may be for to the ER. of may lectin for more whereas transport be by PubMed Scopus Google Scholar). as an endogenous and as an exogenous for for I-MBP in this study with that in our previous study we of some secretory and as I-MBP endogenous ligands, we have an important of the that I-MBP as a cargo intracellular lectin ER-to-Golgi transport. The results with the and and with and oligosaccharides that of a glycoprotein cargo is for binding to I-MBP in the ER, and a or glycoprotein with a oligosaccharide to be the for I-MBP. These results are also with the of and Aebi A. Aebi M. Annu. Rev. Biochem. 2004; 73: 1019-1049Crossref PubMed Scopus (1620) Google that synthesized mannose to the by ER the ER. on our for the association and of I-MBP with oligosaccharides, the of the binding and acid of the binding the physiological of I-MBP as a novel intracellular cargo lectin, a to control the the intracellular lectin and some H. Nat. Biol. 1999; PubMed Scopus Google that to a glycoprotein cargo in the ER and the which is with of its binding J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). Y. Y. N. Y. K. Y. I. Y. K. K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google demonstrated that of binding with a in the and is to the ER, where the to the the the subcellular localization of I-MBP and its physiological strongly that I-MBP may as a cargo intracellular lectin facilitating the ER-to-Golgi transport of which may be associated with quality control in the ER. The subcellular interaction of I-MBP with may or formation, in and in These also the important of cargo the lectin I-MBP its for important I-MBP is in for transport of from the ER, and the subcellular interaction of I-MBP with and are for of the human serum MBP, of for the of pAb, and for