Biology Reference
In-Depth Information
FIGURE 5.2
Generalized model of cellular intoxication by Stxs. (1) Stx holotoxin via its five
B-subunits recognizes and binds to host cell Gb
3
receptors localized in lipid rafts on the surface of
host cells. (2) Shiga toxin undergoes endocytosis and (3) is transported retrograde through the Golgi
apparatus to the lumen of the endoplasmic reticulum (ER). During this time the StxA-subunit may
undergo proteolytic cleavage, possibly by furin present in the endosome or the trans Golgi network
(
Garred et al., 1995a,b
). (4) The proteolytically cleaved StxA1 fragment is detached from the StxA2
fragment and associated StxB-subunits through reduction of an intramolecular disulfide bond.
(5) The StxA1 fragment is then transported to the cytosol (
Tam and Lingwood, 2007
) where it depu-
rinates the alpha sarcin loop of the 28S ribosomal RNA. (6) This damage to the ribosome results
in protein synthesis inhibition, the ribotoxic stress response, and the unfolded protein response all
three of which may contribute to pathology through increased inflammation and/or apoptosis.
to the ER (
Tam and Lingwood, 2007
). Once in the ER, it is presumed that
the disulfide bond is reduced (Step 4) based on the observation that toxins
such as ricin and cholera toxin have been shown to undergo disulfide bond
reduction in this compartment (
Majoul et al., 1997
;
Tsai et al., 2001
;
Bellisola
et al., 2004
;
Spooner et al., 2004
). Furthermore, fluorescently labeled A- and
B-subunits of Stx1 do not separate during retrograde translocation to the ER,
suggesting that Stx disulfide bond reduction does not occur during trans-
port to this compartment (
Tam and Lingwood, 2007
). The free A1 fragment,
which possesses the
N
-glycosidase activity, is then translocated to the cytosol
(Step 5;
LaPointe et al., 2005
;
Yu and Haslam, 2005
;
Tam and Lingwood,
2007
), where its
N
-glycosidase activity results in the cleavage of a single
adenine residue (A4324) located on the α-sarcin/ricin loop of the 28S ribo-
somal RNA (
Obrig et al., 1987
;
Endo et al., 1988
). The depurination of the
ribosome results in cessation of protein synthesis (Step 6;
Endo et al., 1988
;
Saxena et al., 1989
).
Search WWH ::
Custom Search