In filamentous fungi, several lines of experimental evidence indicate that secondary metabolism is triggered by oxidative stress; however, the functional and molecular mechanisms that mediate this association are unclear. The basic leucine zipper (bZIP) transcription factor AtfB, a member of the bZIP/CREB family, helps regulate conidial tolerance to oxidative stress. In this work, we investigated the role of AtfB in the connection between oxidative stress response and secondary metabolism in the filamentous fungus Aspergillus parasiticus. This well characterized model organism synthesizes the secondary metabolite and carcinogen aflatoxin. Cellular response to oxidative stress in vertebrates, plants, and fungi is of fundamental importance; it enables the cell to survive a variety of extra-and intracellular oxidative stressors. An uncontrolled increase in reactive oxygen species (ROS) 4 in mammalian cells is associated with various pathological conditions such as inflammation and cardiovascular and neurodegenerative disorders, including hypertension, atherosclerosis, Parkinson disease, and Alzheimer disease; oxidative stress is also linked to premature aging and cancer (1-10). A detailed understanding of the regulatory network that coordinates the cellular response to oxidative stress will enable better control over its detrimental impacts on humans.As a part of the response to oxidative stress, transcription factors activated directly or indirectly by ROS bind to the promoters of specific genes that trigger defense and signaling related activities. In mammalian cells, Drosophila, Caenorhabditis elegans, and yeast, response to oxidative stress is mediated by an evolutionarily conserved bZIP transcription factor Nrf2 that binds as a heterodimer with Maf or ATF4 to antioxidantresponse elements in the promoters of more than 200 mammalian genes (11-16). Signaling pathways that involve PKC, PI3K, and MAPK participate in Nrf2 activation under ROS exposure. In Arabidopsis, 175 genes were demonstrated to be regulated by hydrogen peroxide, including genes with MYB and AP-1-response elements (17). 140 core stress-related genes were identified in Schizosaccharomyces pombe (18,19).Filamentous fungi in the genus Aspergillus must cope with ROS during their growth and development. Genetic and biochemical studies shed light on the role of ROS in fungal defense, pathogenicity, and development and suggest that fungi use similar stress response pathways as mammalian and plant cells (20 -24). The transcription factors AP-1, AtfA, and AtfB (all members of the basic leucine zipper (bZIP) transcription factor family) have been identified as major players in providing conidia with resistance to oxidative stress in aspergilli. Saccharomyces cerevisiae yap-1 is an ortholog of mammalian AP-1 (25-27). A yap-1 ortholog in Aspergillus parasiticus (ApyapA) is reported to regulate the timing of ROS accumulation, conidiospore development, and stress tolerance in conidiospores (26,27). AtfA, an ortholog of S. pombe Atf1, controls conidial respon...