Journal
BIOCHEMICAL JOURNAL
Volume 403, Issue -, Pages 97-108Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20060819
Keywords
flavocytochrome b(558); glycosylation; haem spectrum; NADPH oxidase 3 (Nox3); Nox organizer 1 (NOXO1); p22(phos)
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Funding
- NHLBI NIH HHS [R01 HL045635, HL53592, R01 HL053592] Funding Source: Medline
- NIAID NIH HHS [R01 AI026711, R56 AI034879, AI34879, R01 AI26711, R01 AI034879] Funding Source: Medline
- BLRD VA [I01 BX000513] Funding Source: Medline
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Otoconia are small biominerals in the inner ear that are indispensable for the normal perception of gravity and motion. Normal otoconia biogenesis requires Nox3, a Nox (NADPH oxiclase) highly expressed in the vestibular system. In HEK-293 cells (human embryonic kidney cells) transfected with the Nox regulatory subunits NoxO1 (Nox organizer 1) and NoxA1 (Nox activator 1), functional murine Nox3 was expressed in the plasma membrane and exhibited a haem spectrum identical with that of Nox2, the electron transferase of the phagocyte Nox. In vitro Nox3 cDNA expressed an similar to 50 kDa primary translation product that underwent N-linked glycosylation in the presence of canine microsomes. RNAi (RNA interference)-mediated reduction of endogenous p22(phox), a subunit essential for stabilization of Nox2 in phagocytes, decreased Nox3 activity in reconstituted HEK-293 cells. p22(phox) co-precipitated not only with Nox3 and NoxO1 from transfectants expressing all three proteins, but also with NoxO1 in the absence of Nox3, indicating that p22(phox) physically associated with both Nox3 and with NoxO1. The plasma membrane localization of Nox3 but not of NoxO1 required p22(phox). Moreover, the glycosylation and maturation of Nox3 required p22(phox) expression, suggesting that p22(phox) was required for the proper biosynthesis and function of Nox3. Taken together, these studies demonstrate critical roles for p22(phox) at several distinct points in the maturation and assembly of a functionally competent Nox3 in the plasma membrane.
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