New Paper Describes Dual Rac2 Regulatory Role
By Jason Socrates Bardi
In a new Nature Immunology paper that is both the
culmination of several years of research and a roadmap for
future inquiries, The Scripps Research Institute (TSRI) Professor
Gary Bokoch and Research Associate Becky Diebold describe
the molecular details of the regulation of NADPH oxidase by
the protein Rac2.
For the past 10 years weve been trying to find
the role of Rac2 in regulating NADPH oxidase function,
says Bokoch, whose immunology laboratory primarily studies
GTP binding proteins involved in signal transduction. "Understanding
this mechanism will have a lot of different implications for
many areas of research."
NADPH oxidase is a multisubunit enzyme that assembles on
the surface of various cell types, including phagocytic leukocytes,
the blood cells that destroy foreign pathogens in an innate
immune response. The pathogens are engulfed by the leukocytes
and then are destroyed by the NADPH oxidases, which blast
them with highly reactive superoxide anions.
These NADPH oxidases must be tightly regulated or else they
will "shoot" indiscriminately, oxidizing normal cells and
damaging healthy tissue. Phagocytic leukocytes regulate the
NADPH oxidase complexes by segregating the individual components,
bringing the subunits together only when needed during an
immune response. Rac2 apparently provides an additional level
of regulation, controlling subsequent oxidant formation by
a two-step molecular mechanism.
The active subunit of the NADPH complex is the heterodimer
protein cytochrome b, which binds a heme and facilitates an
electron cascade that produces the superoxide molecules. When
the cell is not destroying foreign bodies, the cytochrome
b subunit stands alone in the membrane, unloaded as it were.
But when it engulfs a pathogen, the small GTP binding protein
Rac2 is activated and, separately but simultaneously, translocates
to the cellular membrane along with p47 and p67, other cytosolic
oxidase components, to "load" the oxidase.
Diebold and Bokoch also demonstrate that Rac2 regulates
cytochrome b directly through a physical interaction involving
a unique Rac "insert domain." This results in the first step
in the overall electron transfer reaction. The second step
requires Rac2 to additionally interact with p67 to finally
generate superoxide. This dual regulatory role for Rac2 had
not been previously known.
The researchers believe the findings are most relevant to
inflammation, atherosclerosis, and even cancer because non-inflammatory
cells also carry NADPH oxidases. The capability to modulate
oxidant production without totally disarming the protective
leukocyte immune response could provide an improved therapeutic
approach to diseases such as arthritis, cardiac tissue damage
associated with heart attack, and atherosclerosis. The present
work may also provide clues to elucidating the mechanisms
operative in other signaling systems in which the Rac2 protein
plays a direct regulatory role.
The article, "Molecular basis for Rac2 regulation of phagocyte
NADPH oxidase," by Becky A. Diebold and Gary M. Bokoch, appears
in the March 2001 issue of the journal Nature Immunology.