Upstream Regulation of Development and Secondary Metabolism in Aspergillus Species

Abstract

In filamentous fungal Aspergillus species, growth, development, and secondary metabolism are genetically programmed biological processes, which require precise coordination of diverse signaling elements, transcription factors (TFs), upstream and downstream regulators, and biosynthetic genes. For the last few decades, regulatory roles of these controllers in asexual/sexual development and primary/secondary metabolism of Aspergillus species have been extensively studied. Among a wide spectrum of regulators, a handful of global regulators govern upstream regulation of development and metabolism by directly and/or indirectly affecting the expression of various genes including TFs. In this review, with the model fungus Aspergillus nidulans as the central figure, we summarize the most well-studied main upstream regulators and their regulatory roles. Specifically, we present key functions of heterotrimeric G proteins and G protein-coupled receptors in signal transduction), the velvet family proteins governing development and metabolism, LaeA as a global regulator of secondary metabolism, and NsdD, a key GATA-type TF, affecting development and secondary metabolism and provide a snapshot of overall upstream regulatory processes underlying growth, development, and metabolism in Aspergillus fungi.

Keywords: Aspergillus; G proteins; NsdD; development; secondary metabolism; upstream regulators; velvet regulators.

Figure 1

A schematic overview of upstream regulation in Aspergillus species. (A) The heterotrimeric G protein-mediated signaling pathway, initiated by binding of ligands or signals to the corresponding G-protein coupled receptors (GPCRs), relays external environmental signals inside the cell and initiates downstream signaling pathway(s): protein kinase A (PKA), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). As a result, the expression of genes encoding upstream regulators changed either up-regulated or down-regulated, which in turn affects expression levels of various downstream genes. Fungi efficiently control their growth, development, and metabolism through these signal transduction pathways. (B) Three different types of well-studied upstream regulations occurred by the velvet family regulators (developmental regulators), LaeA (a global regulator of secondary metabolism), and NsdD (a key regulator of asexual/sexual development). Solid line represents an activating role and dotted line represents a regulating role (either activating or repressing).

Figure 2

A schematic diagram of heterotrimeric G protein-mediated signaling pathway. Upon the recognition of external ligands, a G protein-coupled receptor (GPCR) is sensitized and interacts with a nearby G protein. Then, G proteins become active by the interaction with GTP and initiate downstream signaling pathway(s): PKA, MAPK, and PKC. This signal transduction results in the differential expression of genes involved in growth, development, morphogenesis, mating, metabolism, virulence, and mycotoxin biosynthesis. The activated G proteins are then negatively controlled by regulators of G protein signaling (RGS) and become inactive again.

Figure 3

Heterotrimeric G protein-mediated signaling pathway in A. nidulans. In A. nidulans, two Gα subunits (FadA and GanB) regulate vegetative growth, development, and mycotoxin production via PKA pathway when they are in the activated state. The regulators of G protein signaling (RGS) FlbA and RgsA turn activated FadA and GanB back into the inactive state, respectively. RicA is a GDP/GTP exchange factor involved in the activation of G protein subunits.

Figure 4

Domain architecture of the velvet regulators in A. nidulans and A. flavus. VD: velvet domain, NLS: Nuclear localization signal, NES: nuclear export signal, PEST: Proline (P)-, glutamic acid (E)-, serine (S)-, and threonine (T)-rich sequence, TAD: transcription activation domain, aa: amino acids.

Figure 5

The functions of velvet family proteins in Aspergillus species. This model is adopted and modified from [82]. VeA enters the nucleus together with VelB and the importin-α KapA in the dark. In the nucleus, velvet family proteins and LaeA can form three different complexes depending on the presence or absence of light: VelB-VosA, VelB-VeA, and VelB-VeA-LaeA. These complexes regulate different biological processes.

Figure 6

The functions of LaeA in Aspergillus. See the “LaeA, a Global Regulator of Secondary Metabolism” section.

Figure 7

A genetic model for growth, developmental, and metabolic control in Aspergillus. An arrow with a solid line indicates a positive regulation (activation) in a relationship, an arrow with a dotted line indicates an unspecified regulation (can be activating or repressing), and a blunt-ended line indicates a repressive role in the relationship.