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family members are themselves regulated by different protein complexes which
ubiquitinate them, promoting proteasomal degradation ( Figure 15.3 A and C).
One of them is the Skp1-Cullin1-F-box protein (SCF) complexes, a subgroup
of the larger Cullin Ring Ubiquitin ligase (CRL) family ( Starostina and Kipreos,
2012 ). The SCF ubiquitination activity is stimulated by the binding of NEDD8
(neddylation) to cullins and by preventing the interaction between cullin and its
inhibitor CAND1 ( Duda et al., 2008 ).
A subset of EPEC and EHEC strains are able to block cells in G1/S and
G2/M phases ( Marches et al., 2003 ; Morikawa et al., 2010 ). The cell cycle
arrest has been linked to the effector Cif which adopts a papain-like hydrolytic
fold with a Cys-His-Asp/Asn/Glu/Gln catalytic triad ( Hsu et al., 2008 ). Dur-
ing infection, Cif is targeted to the nuclear and perinuclear regions where it
interacts with NEDD8, deamidating NEDD8 at Gln40 ( Cui et al., 2010 ; Mori-
kawa et al., 2010 ). Neddylation of SCF with deamidated NEDD8 impairs the
ubiquitin ligase activity of the neddylated complex. SCF substrates (p21, p27,
Nrf-2, HIF-α, Cyclin D1, Cdt1) ( Cui et al., 2010 ; Jubelin et al., 2010 ; Morikawa
et al., 2010 ), accumulate in cells, blocking the G1/S and G2/M phase transitions
( Figure 15.3 B and D). Importantly, the role of Cif has not been yet determined
during in vivo infection.
The Anaphase Promoting Complex/Cyclosome ubiquitin ligases (APC/C)
control the progression and the exit of mitosis. Like the SCF, the APC/C are part
of the CRL family and control a large number of substrates through ubiquitina-
tion, such as Cyclin B which is destroyed after anaphase. Among the APC/C,
two complexes are involved at different stages of mitosis. Binding of Cdc20
to APC/C (APC/C cdc20 ) allows the initiation and progression of mitosis while
binding of Cdh1 to APC/C (APC/C Cdh1 ) activates the APC/C and ubiquitinates
Cdc20 to inactivate APC/C cdc20 allowing the exit of mitosis. During G1 phases,
Cdh1 is then inactivated. APC/C activation like the SCF is tightly controlled
to avoid unscheduled degradation of substrate. The Early mitotic inhibitor 1
(Emi1) inhibits APC/C cdc20 by binding the newly synthesized Cdc20. During the
prophase, Emi1 is phophorylated by Plk1 allowing the activation of APC/Cdc20
complex. Like Emi1, MAD2 (at spindle assembly checkpoint) and MAD2B
(during G2/M phase) inhibit mainly APC/C cdc20 and APC/C Cdh1 respectively
( Pfleger et al., 2001 ) ( Figure 15.3 E).
The translocon protein IpaB of Shigella can interact during infection with
MAD2B but not with MAD2 and Emi1 ( Iwai et al., 2007 ). Interestingly,
MAD2B shares a region of similar sequence similarity with IpgC (aa 61-70),
the IpaB chaperone. Interaction between IpaB and MAD2B decreases the bind-
ing of MAD2B to APC/C Cdh1 and induces an unscheduled activation of APC/
C Cdh1 . This activation leads to the degradation of Cdc20, Plk1, and Cyclin B1,
all protein substrates of the APC/C, and blocks the cell at G2/M phase ( Iwai
et al., 2007 ) ( Figure 15.3 F). Cell cycle arrest induced by IpaB during Shigella
infection of rabbit intestinal ileal loops has been shown to play an important
role in prolonging Shigella colonization of the tissues ( Iwai et al., 2007 ). Impor-
tantly, cell cycle arrest induces cell death.
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