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Vol. 15, Issue 10, 4522-4531, October 2004

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Old Yellow Enzyme Protects the Actin Cytoskeleton from Oxidative Stress

Department of Biochemistry and Molecular Biology, State University of New York, Upstate Medical University, Syracuse, NY 13210

Submitted June 3, 2004; Accepted July 27, 2004
Monitoring Editor: David Drubin

Old Yellow Enzyme (OYE) has long served as a paradigm for the study of flavin-containing NADPH oxido-reductases and yet its physiological role has remained a mystery. A two-hybrid interaction between Oye2p and actin led us to investigate a possible function in the actin cytoskeleton. We found that oye deletion strains have an overly elaborate actin cytoskeleton that cannot be attributed to changes in actin concentration but likely reflect stabilization of actin filaments, resulting in excessive actin assembly. Cells expressing the actin mutant act1-123p, which has a weakened interaction with Oye2p, show comparable defects in actin organization to the oye deletion strain that can be suppressed by overexpression of Oye2p. Similarly, mutation of either conserved cysteine of the potential disulfide pair Cys285-Cys374 in actin completely suppresses the actin organization defect of the oye phenotype. Strains lacking Oye function are also sensitive to oxidative stress as induced by H₂O₂, menadione, and diamide treatment. Mutation of either Cys285 or Cys374 of actin suppresses the sensitivity of oye strains to oxidative stress and in fact confers super-resistance to oxidative stress in otherwise wild-type strains. These results suggest that oxidative damage to actin, like that which has been observed in irreversibly sickled red blood cells, may be a general phenomenon and that OYE functions to control the redox state of actin thereby maintaining the proper plasticity of the actin cytoskeleton. In addition to uncovering a long sought biological function for Old Yellow Enzyme, these results establish that cellular sensitivity to oxidative stress can in part be directly attributed to a specific form (C285-C374 disulfide bond formation) of oxidative damage to actin.

Abbreviations used: AD, activation domain; DBD, DNA binding domain; FMN, flavin mononucleotide; ISC, irreversibly sickled red blood cell; OYE, Old Yellow Enzyme; ROS, reactive oxygen species; RSC, reversibly sickled red blood cell.

^* Corresponding author. E-mail address: ambergd{at}upstate.edu.

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