PerspectiveDevelopmental Biology

Sex and Poison in the Dark

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Science  13 Jun 2008:
Vol. 320, Issue 5882, pp. 1430-1431
DOI: 10.1126/science.1160123

Filamentous fungi are very successful organisms on our planet because of their metabolic versatility and potential to adapt to and survive extreme conditions. In this context, one important feature is their ability to produce different types of spores, for their dissemination in the environment and for resisting harsh conditions (1, 2). Another factor is their success in chemical warfare—fungi produce molecules that help them to compete with other microorganisms (2). The best-known of these compounds are antibiotics, which can benefit one microorganism by inhibiting the growth of others. On the other hand, several other fungal metabolites, such as mycotoxins, cause millions of dollars in losses every year due to contaminated food and animal feed. If ingested by humans, mycotoxins, such as aflatoxin, may cause cancer or even death. Most interestingly, the phenomena of spore development and secondary metabolism are genetically linked (3). On page 1504 of this issue, Bayram et al. (4) unravel this association at a molecular level in the model fungus Aspergillus nidulans and show how this connection is controlled by light.

Most research with the filamentous fungus A. nidulans involves a strain in which the gene encoding the light-responsive protein VeA is mutated (5). A. nidulans develops asexually in light and sexually in the dark, and a veA mutation causes a shift from sexual to asexual spore formation and renders asexual sporulation independent of light. Genetic data thus suggested that VeA regulates light-dependent development. In addition to this role, VeA controls secondary metabolism—the production of molecules that are not absolutely required for the survival of the organism (such as antibiotics and mycotoxins) (3, 6). For example, in the presence of light, A. nidulans produces less of the aflatoxin-related compound sterigmatocystin.

Orthologs of VeA have been characterized in several fungi, where the dual function in morphological and chemical differentiation appears to be conserved (79). Cloning of the veA gene reveals no indication that it encodes a transcriptional regulator or a light sensor (6, 10). However, VeA contains sequences for nuclear targeting and for fast protein turnover. VeA is found in both the cytoplasm and the nucleus, where it accumulates especially in the dark (11). Defects in the control of protein degradation impair the coordination of development and secondary metabolism in the presence or absence of light (12).

The genetic regulation of secondary metabolism is well studied in A. nidulans. Unlike most primary metabolism genes, genes encoding secondary metabolites are clustered in the genome (13). Expression of several of those gene clusters is coordinately regulated by a single protein, LaeA (14, 15). This global regulator is constitutively present in the nucleus and is presumably a methyltransferase, which modifies the chromatin structure of target gene clusters and activates their expression. The open question concerned how development and secondary metabolism are coupled and which role VeA and LaeA may play.

Bayram et al. have now solved this puzzle, showing that VeA forms a protein complex with VelB (a VeA-like protein) and LaeA. VeA and VelB appear to interact already in the cytoplasm and travel together into the nucleus to associate with LaeA. The trimeric protein complex was identified when A. nidulans was grown in the dark. Under light conditions, the VeA concentration in the cell was lower compared to that in the dark, and VeA interacted only with VelB (see the figure). Thus, the concentration of VeA in the nucleus appears to be one crucial parameter for secondary metabolite production and induction of the sexual developmental cycle. Because LaeA does not control sexual development, it is likely that other proteins are interacting with VeA and/or VelB to trigger this pathway.

Shifts in the light.

Whereas asexual development of the fungus A. nidulans is stimulated by light, sexual development and secondary metabolite (mycotoxin) formation are repressed. The VeA-VelB protein complex plays a central role in transmitting the light signal to signaling pathways that control gene expression.

PHOTO CREDITS: SCANNING ELECTRON MICROGRAPHS BY M. KRUEGER, R. WEBER, AND R. FISCHER

This raises the question of how a light signal is transmitted to VeA. There are three possible upstream factors: a phytochrome, FphA; two blue-light receptor systems, LreA and LreB; and the cryptochrome, CryA (1618). Although FphA interacts with VeA in the nucleus (16), a direct connection between any of the light regulators and LaeA has not been discovered through the biochemical approach of Bayram et al. This may indicate that interactions of VeA with light regulators are of a transient nature or that different protein interactions or protein complexes occur at different times in the cell. Whether and how the light regulators control the concentration or the activity of VeA is not yet known.

The challenge for future research will be to define specific functions for VeA and VelB in the discovered protein complex and to determine whether and how the light regulators are interlinked with the LaeA function. Insights into light signaling in A. nidulans may help to control mycotoxin formation or increase penicillin production.

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