Fungal G-Protein-Coupled Receptors: A Promising Mediator of the Impact of Extracellular Signals on Biosynthesis of Ochratoxin A

Abstract

G-protein-coupled receptors (GPCRs) are transmembrane receptors involved in transducing signals from the external environment inside the cell, which enables fungi to coordinate cell transport, metabolism, and growth to promote their survival, reproduction, and virulence. There are 14 classes of GPCRs in fungi involved in sensing various ligands. In this paper, the synthesis of mycotoxins that are GPCR-mediated is discussed with respect to ligands, environmental stimuli, and intra-/interspecific communication. Despite their apparent importance in fungal biology, very little is known about the role of ochratoxin A (OTA) biosynthesis by Aspergillus ochraceus and the ligands that are involved. Fortunately, increasing evidence shows that the GPCR that involves the AF/ST (sterigmatocystin) pathway in fungi belongs to the same genus. Therefore, we speculate that GPCRs play an important role in a variety of environmental signals and downstream pathways in OTA biosynthesis. The verification of this inference will result in a more controllable GPCR target for control of fungal contamination in the future.

Keywords: G protein-coupled receptors; ochratoxin A; oxylipin; quorum sensing; trans-kingdom; transcription factor.

FIGURE 1

Extracellular signals regulate downstream pathways by activating G protein signaling and, thus, influence cellular behavior.| Different classes of GPCRs sense various extracellular factors, which include ligands, environmental cues, and communication signals that bind to the GPCR; this causes GDP-GTP exchange on the Gα protein and dissociation of Gα and Gβγ. Both the Gα-GTP and Gβγ dimers may trigger respective downstream signal cascades, which include the cAMP-activated Protein Kinase A (PKA) pathway, mitogen-activated protein kinase (MAPK) cascades pathway, and the phospholipase C (PLC) pathway. This process influences cellular growth, reproduction, metabolism, virulence, and stress responses. GTP hydrolysis by the Gα subunit results in the reassociation of Gα-GDP with the Gβγ dimer and GPCR, which completes the G protein cycle. The Regulator of G-protein Signaling (RGS) proteins can inactivate G protein signaling rapidly by increasing intrinsic GTPase activity of GTP-bound Gα subunits. In this figure, dashed arrows with the question mark (?) indicates hypothetical interactions.

FIGURE 2

Environmental factors and associated regulatory elements that affect OTA biosynthesis through cluster-specific transcription factors.| Through various global transcription factors or specific pathways, related environmental cues affect the regulation of OTA gene clusters, which contain four highly conserved biosynthetic genes (pks, nrps, hal/chl, p450) and a cluster-specific, transcription factor gene (bZIP). bZIP plays a pivotal role in processing various environmental signals for a carbon source (CreA transcription factor and the carbon catabolite repression pathway), a nitrogen source (AreA transcription factor and the nitrogen catabolite repression pathway), light (Velvet complex proteins, VelB-VeA-LaeA, and the global regulator VosA), temperature and humidity, redox status (Yap transcription factor and ROS), and osmotic stress (the high osmolarity glycerol system). At the same time, there are also some examples where G protein pathways are partly involved in the perception of environmental cues, such as Gα(GanB) and PKA (PkaA) in A. nidulans and GPCR (NopA) in A. fumigatus. In this figure, the black solid arrows indicate connections verified in OTA-producing fungi; the gray solid arrows indicate connections that have been verified in other toxin-producting fungi, but not verified in OTA-producting fungi; and the gray dashed arrows indicate possible, yet unproven, connections.

FIGURE 3

Hypothetical model of mediated communication of G-protein-coupled receptors between fungi and their hosts.| (A) Fungal lipoxygenase (Lox) and psi-producing oxygenases (Ppo) or reactive oxygen species (ROS) can catalyze the oxidation of fatty acids (FAs) to oxylipins, which affect fungal behavior through downstream pathways. Different species of fungi can sense oxylipins secreted in vitro by GPCRs, which regulate cell growth, reproduction, mycotoxins, and apoptosis. (B) Fungal lipases are secreted into plant cells where fatty acid substrates are cleaved and processed by fungi- secreted lipoxygenases and/or plant lipoxygenases for oxylipin production. Plant-produced oxylipins are perceived and exploited by fungi to regulate GPCR-mediated behavior. (C) In mammalian cells, different signals from microbial-derived oxylipids, mediate inflammatory responses, and fungi can affect host physiology through GPCRs. It is also possible that mammalian oxylipins affect fungal activity. All fungal lipases and oxylipins are orange, all plant lipases and oxylipins are green, mammalian oxylipins are red. Dashed arrows with the question mark (?) indicates hypothetical interactions, and solid arrows represent proven interactions.