Abstract
Fungal basic leucine zipper (bZIP) transcription factors mediate responses to oxidative stress. The ability to regulate stress response pathways in Aspergillus spp. was postulated to be an important virulence-associated cellular process, because it helps establish infection in humans, plants, and animals. Previous studies have demonstrated that the fungal transcription factor AtfB encodes a protein that is associated with resistance to oxidative stress in asexual conidiospores, and AtfB binds to the promoters of several stress response genes. Here, we conducted a gene silencing of AtfB in Aspergillus parasiticus, a well-characterized fungal pathogen of plants, animals, and humans that produces the secondary metabolite and carcinogen aflatoxin, in order to determine the mechanisms by which AtfB contributes to virulence. We show that AtfB silencing results in a decrease in aflatoxin enzyme levels, the down-regulation of aflatoxin accumulation, and impaired conidiospore development in AtfB-silenced strains. This observation is supported by a decrease of AtfB protein levels, and the down-regulation of many genes in the aflatoxin cluster, as well as genes involved in secondary metabolism and conidiospore development. Global expression analysis (RNA Seq) demonstrated that AtfB functionally links oxidative stress response pathways to a broader and novel subset of target genes involved in cellular defense, as well as in actin and cytoskeleton arrangement/transport. Thus, AtfB regulates the genes involved in development, stress response, and secondary metabolism in A. parasiticus. We propose that the bZIP regulatory circuit controlled by AtfB provides a large number of excellent cellular targets to reduce fungal virulence. More importantly, understanding key players that are crucial to initiate the cellular response to oxidative stress will enable better control over its detrimental impacts on humans.
Highlights
The basic leucine zipper transcription factors are highly conserved in eukaryotes, and play critical roles in stress response pathways
We proposed that AtfB integrates secondary metabolism and the cellular response to oxidative stress [2]
The current study demonstrates that AtfB is a master regulator of at least three functional networks, including those involved in secondary metabolism (SM), stress response (SR), and conidiospore development (CD)
Summary
The basic leucine zipper (bZIP) transcription factors are highly conserved in eukaryotes, and play critical roles in stress response pathways. These proteins are able to form homodimers or heterodimers, Toxins 2017, 9, 287; doi:10.3390/toxins9090287 www.mdpi.com/journal/toxins. One of the major objectives of studying the regulatory network that coordinates the cellular response to stress is to enable better control of the detrimental effects of cell dysfunction following oxidative insult. BZIP proteins that belong to the ATF/CREB family, such as AtfA and AtfB, were first characterized relative to their roles in the stress tolerance of Aspergillus oryzae conidiospores [4,6]. Numerous studies established that bZIP proteins help regulate stress response, the extent and the functional significance of the bZIP regulatory network have not been characterized in detail
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