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MBC in Press, published online ahead of print November 22, 2006
Mol. Biol. Cell 10.1091/mbc.E06-08-0731

A more recent version of this article appeared on February 1, 2007
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Submitted on August 21, 2006
Revised on November 13, 2006
Accepted on November 14, 2006

A Regulated Adaptor Function of p40phox: Distinct p67phox Membrane Targeting by p40phox and by p47phox

Takehiko Ueyama,* Toshihiko Tatsuno,* Takumi Kawasaki,* Satoshi Tsujibe,* Yasuhito Shirai,* Hideki Sumimoto,{dagger} Thomas L. Leto,{ddagger} and Naoaki Saito*

*Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan; {ddagger}Molecular Defenses Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; {dagger}Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan

Monitoring Editor: Ralph Isberg

In the phagocytic cell NADPH oxidase (Nox2) system, cytoplasmic regulators (p47phox, p67phox, p40phox, and Rac) translocate and associate with the membrane-spanning flavocytochrome b558, leading to activation of superoxide production. We examined membrane targeting of phox proteins and explored conformational changes in p40[supi]phox that regulate its translocation to membranes upon stimulation. GFP-p40phox translocates to early endosomes, while GFP-p47phox translocates to the plasma membrane in response to arachidonic acid. In contrast, GFP-p67phox does not translocate to membranes when expressed alone, but is dependent on p40phox and p47phox for its translocation to early endosomes or the plasma membrane, respectively. Translocation of GFP-p40phox or GFP-p47phox to their respective membrane-targeting sites is abolished by mutations in their PX domains that disrupt their interactions with their cognate phospholipid ligands. Furthermore, GFP-p67phox translocation to either membrane is abolished by mutations that disrupt its interaction with p40phox or p47phox. Finally, we detected a head-to-tail (PX-PB1 domain) intramolecular interaction within p40phox in its resting state by deletion mutagenesis, cell localization, and binding experiments, suggesting that its PX domain is inaccessible to interact with PI(3)P without cell stimulation. Thus, both p40phox and p47phox function as diverse p67phox‘carrier proteins’ regulated by the unmasking of membrane-targeting domains in distinct mechanisms.

Address correspondence to: Naoaki Saito (naosaito{at}kobe-u.ac.jp)




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