BAP31 and Its Caspase Cleavage Product Regulate Cell Surface Expression of Tetraspanins and Integrin-mediated Cell Survival

BAP31, a resident integral protein of the endoplasmic reticulum membrane, regulates the export of other integral membrane proteins to the downstream secretory pathway. Here we show that cell surface expression of the tetraspanins CD9 and CD81 is compromised in mouse cells from which the Bap31 gene has been deleted. CD9 and CD81 facilitate the function of multiprotein complexes at the plasma membrane, including integrins. Of note, BAP31 does not appear to influence the egress of α5β1 or αvβ3 integrins to the cell surface, but in Bap31-null mouse cells, these integrins are not able to maintain cellular adhesion to the extracellular matrix in the presence of reduced serum. Consequently, Bap31-null cells are sensitive to serum starvation-induced apoptosis. Reconstitution of wild-type BAP31 into these Bap31-null cells restores integrin-mediated cell attachment and cell survival after serum stress, whereas interference with the functions of CD9, α5β1, or αvβ3 by antagonizing antibodies makes BAP31 cells act similar to Bap31-null cells in these respects. Finally, in human KB epithelial cells protected from apoptosis by BCL-2, the caspase-8 cleavage product, p20 BAP31, inhibits egress of tetraspanin and integrin-mediated cell attachment. Thus, p20 BAP31 can operate upstream of BCL-2 in living cells to influence cell surface properties due to its effects on protein egress from the endoplasmic reticulum. BAP31, a resident integral protein of the endoplasmic reticulum membrane, regulates the export of other integral membrane proteins to the downstream secretory pathway. Here we show that cell surface expression of the tetraspanins CD9 and CD81 is compromised in mouse cells from which the Bap31 gene has been deleted. CD9 and CD81 facilitate the function of multiprotein complexes at the plasma membrane, including integrins. Of note, BAP31 does not appear to influence the egress of α5β1 or αvβ3 integrins to the cell surface, but in Bap31-null mouse cells, these integrins are not able to maintain cellular adhesion to the extracellular matrix in the presence of reduced serum. Consequently, Bap31-null cells are sensitive to serum starvation-induced apoptosis. Reconstitution of wild-type BAP31 into these Bap31-null cells restores integrin-mediated cell attachment and cell survival after serum stress, whereas interference with the functions of CD9, α5β1, or αvβ3 by antagonizing antibodies makes BAP31 cells act similar to Bap31-null cells in these respects. Finally, in human KB epithelial cells protected from apoptosis by BCL-2, the caspase-8 cleavage product, p20 BAP31, inhibits egress of tetraspanin and integrin-mediated cell attachment. Thus, p20 BAP31 can operate upstream of BCL-2 in living cells to influence cell surface properties due to its effects on protein egress from the endoplasmic reticulum. BAP31 is an evolutionarily conserved polytopic integral protein of the endoplasmic reticulum (ER) 1The abbreviations used are: ER, endoplasmic reticulum; ECM, extracellular matrix; FBS, fetal bovine serum; FACS, fluorescence-activated cell sorter; PBS, phosphate-buffered saline. membrane implicated in regulating the export of selected membrane proteins from the ER to downstream compartments of the secretory pathway. It forms part of a large BAP hetero-oligomeric complex (1Adachi T., W.W. Schimel K.M. Kim T. Watanabe B. Becker P.J. Nielsen Reth M. EMBO J. 1996; 15: 1534-1541Crossref PubMed Scopus (93) Google Scholar, 2Nguyen M. Breckenridge D.G. Ducret A. Shore G.C. Mol. Cell. Biol. 2000; 20: 6731-6740Crossref PubMed Scopus (104) Google Scholar, 3Ducret A. Nguyen M. Breckenridge D.G. Shore G.C. Eur. J. 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Because BAP31 has also been shown to be an important target of caspases in certain apoptosis pathways (2Nguyen M. Breckenridge D.G. Ducret A. Shore G.C. Mol. Cell. Biol. 2000; 20: 6731-6740Crossref PubMed Scopus (104) Google Scholar, 11Ng. F.W. Nguyen M. Kwan T. Branton P.E. Nicholson D.W. Cromlish J.A. Shore G.C. J. Cell Biol. 1997; 139: 327-338Crossref PubMed Scopus (290) Google Scholar, 12Granville D.J. Carthy C.M. Jiang H. Shore G.C. McManus B.M. Hunt D.W. FEBS Lett. 1998; 437: 5-10Crossref PubMed Scopus (173) Google Scholar, 13Breckenridge D.G. Nguyen M. Kuppig S. Reth M. Shore G.C. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4331-4336Crossref PubMed Scopus (106) Google Scholar, 14Breckenridge D.G. Stojanovic M. Marcellus R.C. Shore G.C. J. Cell Biol. 2003; 160: 1115-1127Crossref PubMed Scopus (467) Google Scholar, 15Chandra D. Choy G. Deng X. Bhatia B. Daniel P. Tang D.G. Mol. Cell. 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Tetraspanins comprise a large 4-spanning transmembrane super family (TM4SF) of proteins, which have been conserved throughout evolution, are ubiquitously expressed, and include the differentiation antigens CD9, CD81, CD82, and CD151 (18Boucheix C. Rubinstein E. Cell Mol. Life Sci. 2001; 58: 1189-1205Crossref PubMed Scopus (542) Google Scholar). Tetraspanins have been functionally implicated in different cellular processes, including cell adhesion, migration, cell signaling, metastasis, and growth (18Boucheix C. Rubinstein E. Cell Mol. Life Sci. 2001; 58: 1189-1205Crossref PubMed Scopus (542) Google Scholar, 19Lagaudriere-Gesbert C. Le Naour F. Lebel-Binay S. Billard Lemichez E. Boquet P. Boucheix C. Conjeaud H. Rubinstein E. Cell. Immunol. 1997; 182: 105-112Crossref PubMed Scopus (140) Google Scholar, 20Feigelson S.W. Grabovsky V. Shamri R. Levy S. Alon R. J. Biol. Chem. 2003; 278: 51203-51212Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 21Hemler M.E. J. 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Of note, p20 BAP31 can also operate upstream of BCL-2 in living cells to egress of tetraspanin to the cell surface and integrin-mediated cell attachment. that the cleavage of BAP31 can regulate important cell surface in cells protected from cell Cell and mouse cell of the Bap31 gene by and into cells D.G. Nguyen M. Kuppig S. Reth M. Shore G.C. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4331-4336Crossref PubMed Scopus (106) Google Scholar). cells with or (10Wang B. Pelletier J. Massaad M.J. Herscovics A. Shore G.C. Mol. Cell. Biol. 2004; 24: 2767-2778Crossref PubMed Scopus (49) Google and the cell at and in with FBS, and and KB epithelial cells BCL-2 cells) have been Scholar). antibodies used in this or BAP31 (10Wang B. Pelletier J. Massaad M.J. Herscovics A. Shore G.C. Mol. Cell. Biol. 2004; 24: 2767-2778Crossref PubMed Scopus (49) Google CD9 mouse (2Nguyen M. Breckenridge D.G. Ducret A. Shore G.C. Mol. Cell. Biol. 2000; 20: 6731-6740Crossref PubMed Scopus (104) Google mouse of and and as D.G. Stojanovic M. Marcellus R.C. Shore G.C. J. 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Pelletier J. Massaad M.J. Herscovics A. Shore G.C. Mol. Cell. Biol. 2004; 24: 2767-2778Crossref PubMed Scopus (49) Google the cell the wild-type the expression of the similar to the of Bap31 in Bap31-null cells to cellular CD81 and CD9 at similar to that of cells, as by In and a in the cell surface of these proteins in cells Bap31 with the that CD9 and at the cell surface in cells, but in Bap31-null cells, in a of the cell CD81 not for this therefore, that BAP31 does not influence the of CD9 and CD81 by these cells but that BAP31 is to maintain expression of CD9 and CD81 at the cell BAP31 Cell to Cell of α5β1 and αvβ3 of the that CD9 and CD81 are adaptors that influence the of integrins at the cell surface, we the and cells for their to integrin-mediated including attachment to the that cell with or of the that is by α5β1 and αvβ3 in cells a cell to and with Bap31-null cells, whereas the cell well to In to CD9 and CD81, expression of the at the cell surface, α5β1 and not different in cell as by Bap31-null cells cells Thus, the of BAP31 cell adhesion to and with on the cell surface expression of α5β1 and αvβ3 integrins. Cell CD9 of to the that the in cell attachment to in the of BAP31 expression of the reduced expression of tetraspanin at the surface of these cells, we the of antibodies known to with the function of that and functionally certain CD9 functions in mouse K. X. K. J. K. 1996; PubMed Google Scholar). to cells, this reduced the of these cells to whereas a control not therefore, the in the integrin-mediated cell attachment that due to of that BAP31 function by tetraspanin expression at the cell BAP31 Cell by Bap31-null and cells are cells, and epithelial cells are known to α5β1 αvβ3 for their attachment to (20Feigelson S.W. Grabovsky V. Shamri R. Levy S. Alon R. J. Biol. Chem. 2003; 278: 51203-51212Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, J.F. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). that these integrins in cells, of cells with which to the of α5β1 or αvβ3 integrins and their with the J.F. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar), cells on in the presence of to and cell adhesion by Thus, BAP31 to facilitate cell attachment to that also the of Bap31-null cells to that of α5β1 function of Bap31 not by of cells, including epithelial cells, for and apoptosis in to as serum these are H. J. Cell Biol. 1994; PubMed Scopus Google Scholar, J. B. Mol. Biol. Cell. 1993; PubMed Scopus Google Scholar). that BAP31 is to maintain at the cell surface that BAP31 also to serum starvation-induced cell by Bap31-null and cells in and their by Bap31-null cells as cell and whereas the of cells and well after of serum In to in cell Bap31-null cells not cells) a of after of to serum which the at which associated with of plasma membrane as by that Bap31-null cells are to apoptosis in to serum and that of wild-type BAP31 in these cells to this in to after of that cell surface expression of α5β1 αvβ3 in cells to serum starvation-induced cell we investigated this in cells in the presence or the of antibodies and which are known to the function of the cells in or with and the after and of apoptosis by the of shown in serum in cells with antibodies to or Thus, interference with α5β1 or αvβ3 in cells wild-type BAP31 the of Bap31-null cells to serum that of cell surface integrins by BAP31 cell survival in to serum of BAP31 of CD9 to the Cell in by is by caspase-8 of the upstream of the apoptosis (2Nguyen M. Breckenridge D.G. Ducret A. Shore G.C. Mol. Cell. Biol. 2000; 20: 6731-6740Crossref PubMed Scopus (104) Google Scholar, 4Wang B. Nguyen M. Breckenridge D.G. Stojanovic M. Clemons P.A. Kuppig S. Shore G.C. J. Biol. Chem. 2003; 278: 14461-14468Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 11Ng. F.W. Nguyen M. Kwan T. Branton P.E. Nicholson D.W. Cromlish J.A. Shore G.C. J. Cell Biol. 1997; 139: 327-338Crossref PubMed Scopus (290) Google Scholar, 14Breckenridge D.G. Stojanovic M. Marcellus R.C. Shore G.C. J. Cell Biol. 2003; 160: 1115-1127Crossref PubMed Scopus (467) Google p20 BAP31 at the ER with BAP31 and, of this a that in and of the organelle to other B. Nguyen M. Breckenridge D.G. Stojanovic M. Clemons P.A. Kuppig S. Shore G.C. J. Biol. Chem. 2003; 278: 14461-14468Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 14Breckenridge D.G. Stojanovic M. Marcellus R.C. Shore G.C. J. 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Chem. 2001; 276: 20340-20345Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar), and major histocompatibility complex class I (7Spiliotis E.T. Manley H. Osorio M. Zuniga M.C. Edidin M. Immunity. 2000; 13: 841-851Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 8Paquet M.E. Cohen-Doyle M. Shore G.C. Williams D.B. J. Immunol. 2004; 172: 7548-7555Crossref PubMed Scopus (81) Google Scholar), cell surface expression of the tetraspanins CD9 and CD81 is by BAP31, a resident in the ER membrane. shown of BAP31 not to mouse cells, does have in of complex pathways that are at the cell of BAP31 not in transport defects of α5β1 or αvβ3 integrins to the cell surface, for the compromised transport of CD9 and CD81 tetraspanins the integrity of these integrins. a of BAP31 with to the of apoptosis by serum of these is the that BAP31 for the transmembrane proteins which egress of the ER and be important to the export of newly synthesized integral membrane BAP31 is a target of regulation the cellular to (2Nguyen M. Breckenridge D.G. Ducret A. Shore G.C. Mol. Cell. Biol. 2000; 20: 6731-6740Crossref PubMed Scopus (104) Google Scholar, 4Wang B. Nguyen M. Breckenridge D.G. Stojanovic M. Clemons P.A. Kuppig S. Shore G.C. J. Biol. Chem. 2003; 278: 14461-14468Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). of caspase-8 is a and in cleavage of BAP31 upstream of the its to cell (2Nguyen M. Breckenridge D.G. Ducret A. Shore G.C. Mol. Cell. Biol. 2000; 20: 6731-6740Crossref PubMed Scopus (104) Google Scholar, 4Wang B. Nguyen M. Breckenridge D.G. Stojanovic M. Clemons P.A. Kuppig S. Shore G.C. J. Biol. Chem. 2003; 278: 14461-14468Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 11Ng. F.W. Nguyen M. Kwan T. Branton P.E. Nicholson D.W. Cromlish J.A. Shore G.C. J. Cell Biol. 1997; 139: 327-338Crossref PubMed Scopus (290) Google Scholar). the cleavage is and a of ER a that to F.W. Nguyen M. Kwan T. Branton P.E. Nicholson D.W. Cromlish J.A. Shore G.C. J. Cell Biol. 1997; 139: 327-338Crossref PubMed Scopus (290) Google Scholar, 14Breckenridge D.G. Stojanovic M. Marcellus R.C. Shore G.C. J. Cell Biol. 2003; 160: 1115-1127Crossref PubMed Scopus (467) Google Scholar). In II epithelial cells, of BCL-2 cell by the and ER are D.G. Stojanovic M. Marcellus R.C. Shore G.C. J. Cell Biol. 2003; 160: 1115-1127Crossref PubMed Scopus (467) Google Scholar, D.G. M. Nguyen M. Shore G.C. 2003; PubMed Scopus Google Scholar). we have is that upstream of p20 BAP31 by caspase-8 in living cells BCL-2 influence the integrity of cell surface functions, including integrin-mediated attachment to extracellular BAP31 is as an important regulator of the egress of a of newly synthesized integral membrane proteins of the ER, which quality control (5Schamel W.W. Kuppig S. Becker B. Gimborn K. Hauri H.P. Reth M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 9861-9866Crossref PubMed Scopus (77) Google Scholar, B. Pelletier J. Massaad M.J. Herscovics A. Shore G.C. Mol. Cell. Biol. 2004; 24: 2767-2778Crossref PubMed Scopus (49) Google Scholar), export (7Spiliotis E.T. Manley H. Osorio M. Zuniga M.C. Edidin M. Immunity. 2000; 13: 841-851Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 8Paquet M.E. Cohen-Doyle M. Shore G.C. Williams D.B. J. Immunol. 2004; 172: 7548-7555Crossref PubMed Scopus (81) Google Scholar, K. M. A. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus (49) Google Scholar), and functions. It is part of a large (5Schamel W.W. Kuppig S. Becker B. Gimborn K. Hauri H.P. Reth M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 9861-9866Crossref PubMed Scopus (77) Google Scholar), but is not this cleavage of BAP31, its with (2Nguyen M. Breckenridge D.G. Ducret A. Shore G.C. Mol. Cell. Biol. 2000; 20: 6731-6740Crossref PubMed Scopus (104) Google Scholar, 3Ducret A. Nguyen M. Breckenridge D.G. Shore G.C. Eur. J. 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