Xenopus Death Receptor-M1 and -M2, New Members of the Tumor Necrosis Factor Receptor Superfamily, Trigger Apoptotic Signaling by Differential Mechanisms

Abstract

Signaling through the tumor necrosis factor receptor (TNFR) superfamily can lead to apoptosis or promote cell survival, proliferation, and differentiation. A subset of this family, including TNFR1 and Fas, signals cell death via an intracellular death domain and therefore is termed the death receptor (DR) family. In this study, we identified new members of the DR family, designated xDR-M1 and xDR-M2, in Xenopus laevis. The two proteins, which show high homology (71.7% identity), have characteristics of the DR family, that is, three cysteine-rich domains, a transmembrane domain, and a death domain. To elucidate how members of xDR-M subfamily regulate cell death and survival, we examined the intracellular signaling mediated by these receptors in 293T and A6 cells. Overexpression of xDR-M2 induced apoptosis and activated caspase-8, c-Jun N-terminal kinase, and nuclear factor-κB, although its death domain to a greater extent than did that of xDR-M1 in 293T cells. A caspase-8 inhibitor potently blocked this apoptosis induced by xDR-M2. In contrast, xDR-M1 showed a greater ability to induce apoptosis through its death domain than did xDR-M2 in A6 cells. Interestingly, a general serine protease inhibitor, but not the caspase-8 inhibitor, blocked the xDR-M1-induced apoptosis. These results imply that activation of caspase-8 or serine protease(s) may be required for the xDR-M2- or xDR-M1-induced apoptosis, respectively. Although xDR-M1 and xDR-M2 are very similar to each other, the difference in their death domains may result in diverse signaling, suggesting distinct roles of xDR-M1 and xDR-M2 in cell death or survival. Signaling through the tumor necrosis factor receptor (TNFR) superfamily can lead to apoptosis or promote cell survival, proliferation, and differentiation. A subset of this family, including TNFR1 and Fas, signals cell death via an intracellular death domain and therefore is termed the death receptor (DR) family. In this study, we identified new members of the DR family, designated xDR-M1 and xDR-M2, in Xenopus laevis. The two proteins, which show high homology (71.7% identity), have characteristics of the DR family, that is, three cysteine-rich domains, a transmembrane domain, and a death domain. To elucidate how members of xDR-M subfamily regulate cell death and survival, we examined the intracellular signaling mediated by these receptors in 293T and A6 cells. Overexpression of xDR-M2 induced apoptosis and activated caspase-8, c-Jun N-terminal kinase, and nuclear factor-κB, although its death domain to a greater extent than did that of xDR-M1 in 293T cells. A caspase-8 inhibitor potently blocked this apoptosis induced by xDR-M2. In contrast, xDR-M1 showed a greater ability to induce apoptosis through its death domain than did xDR-M2 in A6 cells. Interestingly, a general serine protease inhibitor, but not the caspase-8 inhibitor, blocked the xDR-M1-induced apoptosis. These results imply that activation of caspase-8 or serine protease(s) may be required for the xDR-M2- or xDR-M1-induced apoptosis, respectively. Although xDR-M1 and xDR-M2 are very similar to each other, the difference in their death domains may result in diverse signaling, suggesting distinct roles of xDR-M1 and xDR-M2 in cell death or survival. Apoptosis plays a crucial role in both the development and the homeostasis of metazoans. Cells die by apoptosis in the developing embryo during morphogenesis and in the adult during tissue turnover or at the end of an immune response. A number of molecules are known to be involved in apoptotic signaling. Intensive investigation of some members of the tumor necrosis factor receptor (TNFR) 1The abbreviations used are: TNFR, tumor necrosis factor receptor; DR, death receptor; MAPK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; NF-κB, nuclear factor-κB; AEBSF, 4-(2-aminoethyl)-benzenesulfonyl fluoride; RT, reverse transcription; RACE, rapid amplification of cDNA ends; LBR, ligand-binding region; DD, death domain; GFP, green fluorescent protein; EGFP, enhanced green fluorescent protein; Z-IETD-FMK, benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethylketone; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TRADD, TNFR1-associated death domain protein; RIP, receptor-interacting protein; HRP, horseradish peroxidase; ORF, open reading frame; PBS, phosphate-buffered saline. superfamily has led to a better understanding of the signaling pathways in apoptosis (1Smith C.A. Farrah T. Goodwin R.G. Cell. 1994; 76: 959-962Abstract Full Text PDF PubMed Scopus (1838) Google Scholar, 2Gruss H.J. Dower S.K. Blood. 1995; 85: 3378-3404Crossref PubMed Google Scholar, 3Baker S.J. Reddy E.P. Oncogene. 1998; 17: 3261-32670Crossref PubMed Scopus (482) Google Scholar). In general, the TNFR superfamily is implicated in diverse biological activities, such as the regulation, not only of cell death, but also of cell proliferation, differentiation, survival, and cytokine production (4Ashkenazi A. Dixit V.M. Science. 1998; 281: 1305-1308Crossref PubMed Scopus (5154) Google Scholar, 5Locksley R.M. Killeen N. Lenardo M.J. Cell. 2001; 104: 487-501Abstract Full Text Full Text PDF PubMed Scopus (3018) Google Scholar). The receptors of this family share a common structural motif in their extracellular region that has been shown to be important for ligand binding; this motif consists of multiple cysteine-rich repeats of ∼30–40 amino acids each (6Naismith J.H. Sprang S.R. Trends Biochem. Sci. 1998; 23: 74-79Abstract Full Text PDF PubMed Scopus (188) Google Scholar). The death receptors (DRs), which make up a subset of the TNFR superfamily, contain in addition a homologous sequence in their cytoplasmic region termed the “death domain” that consists of ∼80 amino acids and is involved in mediating apoptosis signaling (7Itoh N. Nagata S. J. Biol. Chem. 1993; 268: 10932-10937Abstract Full Text PDF PubMed Google Scholar). The best-characterized death receptors are Fas (also called CD95 or Apo1) (8Yonehara S. Ishii A. Yonehara M. J. Exp. Med. 1989; 169: 1747-1756Crossref PubMed Scopus (1429) Google Scholar, 9Trauth B.C. Klas C. Peters A.M. Matzku S. Moller P. Falk W. Debatin K.M. Krammer P.H. Science. 1989; 245: 301-305Crossref PubMed Scopus (1667) Google Scholar) and TNFR1 (also called p55) (10Nophar Y. Kemper O. Brakebusch C. Englemann H. Zwang R. Aderka D. Holtmann H. Wallach D. EMBO J. 1990; 9: 3269-3278Crossref PubMed Scopus (288) Google Scholar). Recently, a number of additional death receptors have been reported, such as DR3 (also called Apo3, WSL-1, or TRAMP) (11Marsters S.A. Sheridan J.P. Donahue C.J. Pitti R.M. Gray C.L. Goddard A.D. Bauer K.D. Ashkenazi A. Curr. Biol. 1996; 6: 1669-1676Abstract Full Text Full Text PDF PubMed Google Scholar, 12Kitson J. Raven T. Jiang Y.P. Goeddel D.V. Giles K.M. Pun K.T. Grinham C.J. Brown R. Farrow S.N. Nature. 1996; 384: 372-375Crossref PubMed Scopus (295) Google Scholar, 13Chinnaiyan A.M. O'Rourke K. Yu G.L. Lyons R.H. Garg M. Duan D.R. Xing L. Gentz R. Ni J. Dixit V.M. Science. 1996; 274: 990-992Crossref PubMed Scopus (531) Google Scholar, 14Bodmer J.L. Schneider P. Tschopp J. Trends Biochem. Sci. 2002; 27: 19-26Abstract Full Text Full Text PDF PubMed Scopus (716) Google Scholar), DR4 (15Pan G. O'Rourke K. Chinnaiyan A.M. Gentz R. Ebner R. Ni J. Dixit V.M. Science. 1997; 276: 111-113Crossref PubMed Scopus (1561) Google Scholar), and DR5 (16Chaudhary P.M. Eby M. Jasmin A. Bookwalter A. Murray J. Hood L. Immunity. 1997; 7: 821-830Abstract Full Text Full Text PDF PubMed Scopus (613) Google Scholar). The death receptors are believed to activate mainly three kinds of signaling cascades: (i) kinase cascades leading to the activation of nuclear factor-κB (NF-κB) (17Karin M. Lin A. Nat. Immunol. 2002; 3: 221-227Crossref PubMed Scopus (2451) Google Scholar), (ii) mitogen-activated protein kinases (MAPK) cascades, including the c-Jun N-terminal kinase (JNK) or p38 cascades (18Schulze-Osthoff K. Ferrari D. Los M. Wesselborg S. Peter M.E. Eur. J. Biochem. 1998; 254: 439-459Crossref PubMed Scopus (861) Google Scholar), and (iii) protease cascades involving the sequential activation of caspases (19Cryns V. Yuan J. Genes Dev. 1998; 12: 1551-1570Crossref PubMed Scopus (1161) Google Scholar). 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Scaffidi C. Bretz J.D. Zhang M. Gentz R. Mann M. Krammer P.H. Peter M.E. Dixit V.M. Cell. 1996; 85: 817-827Abstract Full Text Full Text PDF PubMed Scopus (2741) Google Scholar). The resulting complex facilitates the autocatalytic activation of caspase-8. The active caspase-8 then causes the proteolytic activation of downstream caspases that culminates in the irreversible commitment of the cells to apoptosis (19Cryns V. Yuan J. Genes Dev. 1998; 12: 1551-1570Crossref PubMed Scopus (1161) Google Scholar). More recently, evidence has accumulated that non-caspase proteases such as cathepsis and serine protease(s) are also involved in DR-induced apoptosis (25Foghsgaard L. Wissing D. Mauch D. Lademann U. Bastholm L. Boes M. Elling F. Leist M. Jaattela M. J. Cell Biol. 2001; 153: 999-1010Crossref PubMed Scopus (563) Google Scholar, 26Park I.C. Park M.J. Woo S.H. Lee K.H. Lee S.H. Rhee C.H. Hong S.I. Cytokine. 2001; 15: 166-170Crossref PubMed Scopus (8) Google Scholar). 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Science. 1998; 281: PubMed Scopus Google Scholar), a of the family, is the death-inducing signal complex, and activation can then be through the signaling has been that may two distinct signaling activation M. M. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). members of the TNFR superfamily, including the and factor have been identified in only three members of the TNFR superfamily, M. J. 2001; PubMed Scopus Google Scholar), and number have been in Xenopus laevis. Although these molecules have death domains, has been evidence that promote apoptosis. to elucidate the signaling pathways of apoptosis or cell that through death receptors in new members of the death receptor family, xDR-M1 and xDR-M2, have been this that signaling and activation is by xDR-M1 and xDR-M2 and that xDR-M1 and xDR-M2 in apoptosis through distinct and horseradish and 4-(2-aminoethyl)-benzenesulfonyl and and p38 kinase and Cell Signaling respectively. of xDR-M1 and xDR-M2 Xenopus cDNA S. M. N. S. T. 1997; PubMed Scopus Google Scholar) a xDR-M1 cDNA as a in the by the and as M. Y. N. H. T. Sci. U. S. A. 1993; PubMed Scopus Google Scholar). The xDR-M1 cDNA by in A for sequence homology with xDR-M1 cDNA by the the end of the xDR-M2 cDNA Xenopus cDNA a to the The rapid amplification of cDNA the and both of the open reading of xDR-M1 xDR-M1 cDNA by two and The which a at the end and a at the end of the with and with The resulting an to The of xDR-M2 Xenopus cDNA by two and The which a at the end and a at the end of the with and The resulting a to To of xDR-M1 and xDR-M2, of xDR-M1 or xDR-M2 by and the a The and 1 to and 1 to amino which the ligand-binding the xDR-M1 and of and amino which the transmembrane region and death domain. The of Fas by two and The which a at the end and an at the end of the with and with The resulting a that with and with to and their by the a The S. M. N. T. K. K. 1999; 3: Scopus Google Scholar). The of Xenopus caspase-8 Xenopus cDNA by two and The an to The of by two and To the a that with and The of which number the to an reverse with to the of the cDNA as a for to the xDR-M1 or xDR-M2 cDNA with and reverse or and reverse respectively. The and reverse for xDR-M1 to the 1 and or respectively. Cell and cells in and at 293T cells in and at in a with cells at cells Cells to the of Apoptosis by cells in cells in in phosphate-buffered for and then to in for blocked by with in for The cells then with in for 1 by three and with and for 1 with three examined by The of apoptotic cells by the cells with nuclear the cells. The and at cells for each a and to The blocked with in PBS, with and three with The then with the by enhanced of cells with and the the cell as M. K. M. S. N. K. M. Y. T. K. Cell. Biol. 1999; PubMed Scopus Google Scholar) and by with or 293T cells at cells then with and of the The used to the to the of in each the cells and their the by with as an The in of xDR-M1 and xDR-M2 to a of xDR-M1 cDNA we for a that in the Xenopus cDNA then a Xenopus cDNA a for a sequence similar to xDR-M1 the A cDNA sequence number that showed homology with of the xDR-M1 The which designated xDR-M2, then by Xenopus cDNA to that been the and The and amino of xDR-M1 and xDR-M2 and are shown in cDNA an that a protein of amino The amino of the showed the each xDR-M to have a signal three cysteine-rich a transmembrane domain, and a death domain. a for the signal in and 1 in xDR-M1 and xDR-M2 may proteolytic to a protein with and amino respectively. The transmembrane domains and of xDR-M1 and xDR-M2, respectively. The extracellular domains of the the three cysteine-rich repeats that the TNFR superfamily These cysteine-rich domains to the of the TNFR superfamily members with their The cytoplasmic of xDR-M1 and xDR-M2 death domains that are of some TNFR superfamily members and are involved in apoptosis these molecules to the death receptor family the TNFR The homology (71.7% with each than is and their ligand-binding region and death domains and sequence In general, the DR family members have homology with the of the also similar in the are to a new which we the xDR-M of xDR-M1 and xDR-M2 to the of xDR-M1 or xDR-M2 in The to xDR-M1 or xDR-M2 the of the of the used for xDR-M1 and xDR-M2 the sequence of the for xDR-M1 to contain 1 and the for the xDR-M1 and the reverse for xDR-M1 the sequence for not Although the of the xDR-M2 has not been may be similar to that of the xDR-M1 to be TNFR superfamily The and by that xDR-M1 and xDR-M2 in adult that is, and The xDR-M also in at the of not The of xDR-M1 and xDR-M2 also by in A6 which are In these the for xDR-M1 but not for xDR-M2 xDR-M1 and xDR-M2 to The signaling pathways by the death domains of death receptors are to lead to apoptosis. These pathways are by the of the receptors ligand resulting in the of the death domains with adapter such as and Overexpression of death receptors can induce apoptosis in a (21Chinnaiyan A.M. O'Rourke K. Tewari M. Dixit V.M. Cell. 1995; 81: 505-512Abstract Full Text PDF PubMed Scopus (2161) Google Scholar, 22Boldin M.P. Varfolomeev E.E. Pancer Z. Mett I.L. Camonis J.H. Wallach D.A. J. Biol. Chem. 1995; 270: 7795-7798Abstract Full Text Full Text PDF PubMed Scopus (939) Google Scholar). To the role of xDR-M1 and xDR-M2 in apoptosis, each of the death receptors in 293T cells and in Xenopus A6 cells. In 293T of xDR-M2 as as Fas induced apoptosis in of the cells The apoptotic cells showed the nuclear that is of apoptotic cell death In contrast, of the 293T cells in which xDR-M1 showed this apoptotic A and although the of xDR-M1 and xDR-M2 by of the 293T cells not In A6 of xDR-M1 or its the death domain induced apoptosis to a greater extent than did that of xDR-M2 or its death domain, ligand-binding region of xDR-M1 xDR-M2 apoptosis of or for the Apoptosis by xDR-M2 or receptors caspase-8 in a mediated by adapter such as TRADD, and activate caspase-8. in to the of downstream caspases in a and death (8Yonehara S. Ishii A. Yonehara M. J. Exp. Med. 1989; 169: 1747-1756Crossref PubMed Scopus (1429) Google Scholar). To the activation of caspase-8 plays a crucial role in the of apoptosis, we examined the autocatalytic of caspase-8 induced by the of For the of 293T or A6 cells with caspase-8 and xDR-M1 or xDR-M2, and the caspase-8 activation by with shown in of xDR-M2 but not xDR-M1 activated caspase-8 in 293T cells. The of xDR-M2 its death domain also activated caspase-8, but the the death domain did a role of the death domain in caspase-8. in A6 cells xDR-M1 xDR-M2 of caspase-8 not To the activation of caspase-8 is for the apoptosis induced by xDR-M2, we examined the of a caspase-8 inhibitor, Z-IETD-FMK, and a cytokine A a of the the cell death induced by xDR-M2 in 293T cells. to the cells the cell death and not the to have the apoptosis in A6 cells and not of caspase-8 and serine protease apoptosis induced by xDR-M1 and and 293T cells with of xDR-M2, or Fas the with the of with or a inhibitor, or a serine protease inhibitor, respectively. the cells The the of the of apoptosis and A6 cells with or the with the of with the as in A or that a of the the xDR-M1-induced apoptosis in 293T or A6 cells blocked by the inhibitor as shown in A or respectively. has that tumor necrosis factor-related apoptosis ligand apoptosis can be blocked by a general serine protease inhibitor, AEBSF, in cell I.C. Park M.J. Woo S.H. Lee K.H. Lee S.H. Rhee C.H. Hong S.I. Cytokine. 2001; 15: 166-170Crossref PubMed Scopus (8) Google Scholar). we activation of serine protease(s) is required for the apoptosis by The serine protease inhibitor, AEBSF, the apoptosis induced by xDR-M1 both in 293T and A6 cells and In contrast, the inhibitor the apoptosis induced by xDR-M2 in A6 or 293T cells or by Overexpression of apoptosis induced by death receptors is by the activation of or examined is a difference in signaling xDR-M1 and xDR-M2. For the of 293T cells with the for and xDR-M1 or xDR-M2, and the activation by with an xDR-M2 a greater ability to activate than did xDR-M1 or Fas The inhibitor, the apoptosis induced by xDR-M2 not In A6 activation of or p38 induced by xDR-M1 or xDR-M2 not in or or p38 not xDR-M1 and xDR-M2 important induced by members of the death receptor family is the activation of the factor (17Karin M. Lin A. Nat. Immunol. 2002; 3: 221-227Crossref PubMed Scopus (2451) Google Scholar). To the signaling leading to Xenopus A6 cells and 293T cells with an and xDR-M1 or xDR-M2 In 293T the of xDR-M1 induced activation that of xDR-M2 or Fas activated receptors activated a of that the death domains of xDR-M1 and xDR-M2 to to the activation of These death activation by the of an not In A6 of xDR-M1 and its death domain also activated and xDR-M2 showed a ability to activate than did xDR-M1 In this we have Xenopus designated xDR-M1 and xDR-M2, which new members of the TNFR The share the homology (71.7% with each the known members of the TNFR superfamily The extracellular domains of TNFR superfamily members contain cysteine-rich repeats that a crucial role in to their cognate ligand (1Smith C.A. Farrah T. Goodwin R.G. Cell. 1994; 76: 959-962Abstract Full Text PDF PubMed Scopus (1838) Google Scholar). of xDR-M1 and xDR-M2 are similar to each identity), with their In and or DR4 and DR5 are believed to the ligand, TNFα or TRAIL, P. Tschopp J. PubMed Scopus Google Scholar). is that the ligand may the signaling mediated by xDR-M1 or xDR-M2. The of xDR-M1 and xDR-M2 similar to each in adult In contrast, xDR-M1 in the A6 cell Xenopus by xDR-M2 These results that xDR-M1 and xDR-M2 may be during development or to extracellular To these be to the of xDR-M1 and xDR-M2 by in or has been believed that the sequential activation of caspases the of active caspase-8 is to be crucial for apoptosis by death receptors (8Yonehara S. Ishii A. Yonehara M. J. Exp. Med. 1989; 169: 1747-1756Crossref PubMed Scopus (1429) Google Scholar). have that of proteases may also in apoptosis by TNFα and in some cell (25Foghsgaard L. Wissing D. Mauch D. Lademann U. Bastholm L. Boes M. Elling F. Leist M. Jaattela M. J. Cell Biol. 2001; 153: 999-1010Crossref PubMed Scopus (563) Google Scholar, 26Park I.C. Park M.J. Woo S.H. Lee K.H. Lee S.H. Rhee C.H. Hong S.I. Cytokine. 2001; 15: 166-170Crossref PubMed Scopus (8) Google Scholar). the of caspase-8 and serine protease(s) we have shown that xDR-M1 and xDR-M2 is to induce apoptosis by activation of some serine protease(s) and caspase-8, suggesting distinct roles of xDR-M members in apoptotic signaling. is that TNFα receptors and or receptors DR4 and may distinct roles in and serine protease pathways apoptotic signaling as xDR-M1 and xDR-M2 may The activation of death receptors the of is known to induce the and signaling pathways in addition to the protease The signaling is known to activate signals Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). the activation of is not required for apoptosis H. Goeddel D.V. M. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, L. A.M. J.D. Cell Biol. 1997; 17: PubMed Scopus Google Scholar). In 293T a high activation of xDR-M2 activation not to induce the apoptosis by xDR-M2, a inhibitor the apoptosis not The activation of is believed to be a signal apoptosis that to the of including and which N. T. EMBO J. 1998; 17: PubMed Scopus Google Scholar, Z. H. D. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, A. S. Krammer P.H. S. Cell Biol. 2001; PubMed Scopus Google Scholar). Although of xDR-M2 induced a activation of NF-κB, this activation did not the of apoptosis, the of a of signaling, the signaling not members of the death receptor family can also induce the activation of with apoptosis (11Marsters S.A. Sheridan J.P. Donahue C.J. Pitti R.M. Gray C.L. Goddard A.D. Bauer K.D. Ashkenazi A. Curr. Biol. 1996; 6: 1669-1676Abstract Full Text Full Text PDF PubMed Google Scholar, 12Kitson J. Raven T. Jiang Y.P. Goeddel D.V. Giles K.M. Pun K.T. Grinham C.J. Brown R. Farrow S.N. Nature. 1996; 384: 372-375Crossref PubMed Scopus (295) Google Scholar, 13Chinnaiyan A.M. O'Rourke K. Yu G.L. Lyons R.H. Garg M. Duan D.R. Xing L. Gentz R. Ni J. Dixit V.M. Science. 1996; 274: 990-992Crossref PubMed Scopus (531) Google Scholar, 14Bodmer J.L. Schneider P. Tschopp J. Trends Biochem. Sci. 2002; 27: 19-26Abstract Full Text Full Text PDF PubMed Scopus (716) Google Scholar, P.M. Eby M. Jasmin A. Bookwalter A. Murray J. Hood L. Immunity. 1997; 7: 821-830Abstract Full Text Full Text PDF PubMed Scopus (613) Google Scholar). the role of activation in death receptor-induced cell death or The ability of xDR-M1 to activate than that of xDR-M2 in A6 the than the in 293T cells The activation induced by xDR-M1 or xDR-M2 by the of in the both cell not this difference may be by of and of some adapter that can be xDR-M1 or xDR-M2 signaling The activation of caspase-8, JNK, or by xDR-M receptors its death domain and and not These results that the in caspase-8, JNK, and signaling mediated by xDR-M1 and xDR-M2 are to the death domains in their cytoplasmic In death receptors with adapter proteins, such as and TRADD, through their death The difference in the death domains of xDR-M1 and xDR-M2 their for the adapter resulting in the of diverse signaling. The the death domains of xDR-M1 and xDR-M2 is than that their ligand-binding is to that each death domain with adapter in a distinct leading to the signaling of xDR-M1 and xDR-M2. have adapter molecules Xenopus that share homology with and be to the roles of these molecules in xDR-M signaling. is that xDR-M1 and xDR-M2 distinct roles in the intracellular signaling for apoptosis or survival, resulting in the of diverse the extracellular is of to how xDR-M1 and xDR-M2 are to during which both xDR-M1 and xDR-M2 not To elucidate the of the two be to the of xDR-M1 and xDR-M2 during development and to their cognate for