A bacterial effector targets Mad2L2, an APC inhibitor, to modulate host cell cycling.
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.
Iwai
Hiroki
H
Department of Microbiology and Immunology, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Kim
Minsoo
M
Yoshikawa
Yuko
Y
Ashida
Hiroshi
H
Ogawa
Michinaga
M
Fujita
Yukihiro
Y
Muller
Daniel
D
Kirikae
Teruo
T
Jackson
Peter K
PK
Kotani
Shuji
S
Sasakawa
Chihiro
C
D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000502:physiology; D002455:Cell Division; D004405:Dysentery, Bacillary / Q000473:pathology; D016195:G2 Phase; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007082:Ileum / Q000382:microbiology; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000382:microbiology; D064246:Mad2 Proteins; D008954:Models, Biological; D011233:Precipitin Tests; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism; D012760:Shigella / Q000378:metabolism* / Q000472:pathogenicity; D020798:Two-Hybrid System Techniques; D043743:Ubiquitin-Protein Ligase Complexes / Q000037:antagonists & inhibitors*; D014452:Ubiquitins / Q000032:analysis
D001426:Bacterial Proteins; D018797:Cell Cycle Proteins; C120552:MAD2L2 protein, human; D064246:Mad2 Proteins; D018809:Proliferating Cell Nuclear Antigen; D011506:Proteins; D011994:Recombinant Proteins; D014452:Ubiquitins; C087447:ipaB protein, Shigella; D049452:Green Fluorescent Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D005982:Glutathione Transferase