XAF1 mediates tumor necrosis factor-α-induced apoptosis and X-linked inhibitor of apoptosis cleavage by acting through the mitochondrial pathway

被引:60
作者
Straszewski-Chavez, Shawn L.
Visintin, Irene P.
Karassina, Natasha
Los, Georgyi
Liston, Peter
Halaban, Ruth
Fadiel, Ahmed
Mor, Gil
机构
[1] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, Reprod Immunol Unit, New Haven, CT 06520 USA
[2] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06520 USA
[3] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA
[4] Promega Corp, Madison, WI 53711 USA
[5] Univ Ottawa, Dept Pediat, Ottawa, ON K1H 8M5, Canada
关键词
D O I
10.1074/jbc.M609038200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Tumor necrosis factor-alpha (TNF-alpha) and Fas ligand induce apoptosis by interacting with their corresponding membrane bound death receptors and activating caspases. Since both systems share several components of the intracellular apoptotic cascade and are expressed by first trimester trophoblasts, it is unknown how these cells remain resistant to Fas ligand while sensitive to TNF-alpha. XAF1 (X-linked inhibitor of apoptosis (XIAP)-associated factor 1) is a proapoptotic protein that antagonizes the caspase-inhibitory activity of XIAP. Here, we demonstrated that XAF1 functions as an alternative pathway for TNF alpha-induced apoptosis by translocating to the mitochondria and promoting XIAP inactivation. In addition, we showed that the overexpression of XAF1 sensitized first trimester trophoblast cells to Fas-mediated apoptosis. Furthermore, we also determined that the differential expression of XAF1 in first and third trimester trophoblast cells was due to changes in XAF1 gene methylation. Our results establish a novel regulatory pathway controlling trophoblast cell survival and provide a molecular mechanism to explain trophoblast sensitivity to TNF-alpha and the increased number of apoptotic trophoblast cells observed near term. Aberrant XAF1 expression and/or localization may have consequences for normal pregnancy outcome.
引用
收藏
页码:13059 / 13072
页数:14
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