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Activation mechanisms
Signaling by ROS drives inflammasome activation
Fabio Martinon
Department of Immunology and Infectious Diseases, Harvard School of Public Health,
Boston, MA, USA
DOI 10.1002/eji.200940168
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Figure 1. Examples of ROS generating pathways. (A) During respiration 12% of the
oxygen is partially reduced to O2 " , which
can be converted H2O2 and OH . The major
sites of for production in the mitochondrial
respiratory chain are at complexes I and III.
Complex I accepts electrons from NADH;
these electrons move down an electrochemical gradient through ubiquinone (Q cycle) to
complex III, from complex III to cytochrome c
(C) and from C to complex IV that use the
electrons to reduce molecular oxygen to
water. The mechanisms involved in
generation of O2 " by complex I are poorly
understood. Complex III generate O2 " by
auto-oxidation of ubisemiquinone generated
during the Q cycle, (IM, inner mitochondrial
membrane). (B) NADPH oxidases such as the
NOX2 complex transport electrons across
biological membranes to reduce oxygen to
superoxide. The activation of NOX2 occurs
through a complex series of protein/protein
interactions. Phosphorylation of p47phox leads
to a conformational change allowing its
interaction with p22phox. The localization of
p47phox to the membrane brings p67phox into
contact with NOX2 and also brings the small
subunit p40phox to the complex. Finally, the
GTPase Rac interacts with NOX2. Once
assembled, the complex is active and generates superoxide by transferring an electron
from NADPH in the cytosol to oxygen on the
luminal or extracellular space.
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Concluding remarks
In contradiction with classical PRR,
rather than directly recognizing pathogenic elements, NLRP3/NALP3 seems to
detect oxidative stress produced by
pathogenic insults [43] (Fig. 2). This
model shares similarities with the guard
model in plants. Pathogen-mediated
changes in plant cellular physiology
trigger activation of the R genes, a
family of innate immune sensors that
cope with infections and share structural
similarities with NLRP3/NALP3 [44].
Although the mechanisms involved in
inflammasome activation by oxidative
stress are still unclear, ROS is emerging
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Acknowledgements:
The
author
is
supported by a Human Frontier Science
Program long-term fellowship.
Conflict of interest: The author declares no
financial or commercial conflict of interest.
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