A bacterial effector targets Mad2L2, an APC inhibitor, to modulate host cell cycling

被引:120
作者
Iwai, Hiroki
Kim, Minsoo
Yoshikawa, Yuko
Ashida, Hiroshi
Ogawa, Michinaga
Fujita, Yukihiro
Muller, Daniel
Kirikae, Teruo
Jackson, Peter K.
Kotani, Shuji
Sasakawa, Chihiro
机构
[1] Univ Tokyo, Inst Med Sci, Minato Ku, Dept Microbiol & Immunol, Tokyo 1088639, Japan
[2] Univ Tokyo, Inst Med Sci, Dept Infect Dis Control, Minato Ku, Tokyo 1088639, Japan
[3] Univ Tokyo, Inst Med Sci, Int Res Ctr Infect Dis, Minato Ku, Tokyo 1088639, Japan
[4] Tokyo Med & Dent Univ, Med Res Inst, Dept Mol Cytogenet, Bunkyo Ku, Tokyo 1130034, Japan
[5] Int Med Ctr Japan, Inst Res, Dept Infect Dis, Shinjuku Ku, Tokyo 1628655, Japan
[6] Genentech Inc, San Francisco, CA 94080 USA
[7] Japan Sci & Technol Agcy, CREST, Kawaguchi 3320012, Japan
基金
日本科学技术振兴机构; 日本学术振兴会;
关键词
D O I
10.1016/j.cell.2007.06.043
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
The gut epithelium self-renews every several days, providing an important innate defense system that limits bacterial colonization. Nevertheless, many bacterial pathogens, including Shigella, efficiently colonize the intestinal epithelium. Here, we show that the Shigella effector IpaB, when delivered into epithelial cells, causes cell-cycle arrest by targeting Mad2L2, an anaphase-promoting complex/cyclosome ( APC) inhibitor. Cyclin B1 ubiquitination assays revealed that APC undergoes unscheduled activation due to IpaB interaction with the APC inhibitor Mad2L2. Synchronized HeLa cells infected with Shigella failed to accumulate Cyclin B1, Cdc20, and Plk1, causing cell-cycle arrest at the G2/M phase in an IpaB/Mad2L2-dependent manner. IpaB/Mad2L2-dependent cell-cycle arrest by Shigella infection was also demonstrated in rabbit intestinal crypt progenitors, and the IpaB-mediated arrest contributed to efficient colonization of the host cells. These results strongly indicate that Shigella employ special tactics to influence epithelial renewal in order to promote bacterial colonization of intestinal epithelium.
引用
收藏
页码:611 / 623
页数:13
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