Carbon Catabolite Repression in Filamentous Fungi

Abstract

Carbon Catabolite Repression (CCR) has fascinated scientists and researchers around the globe for the past few decades. This important mechanism allows preferential utilization of an energy-efficient and readily available carbon source over relatively less easily accessible carbon sources. This mechanism helps microorganisms to obtain maximum amount of glucose in order to keep pace with their metabolism. Microorganisms assimilate glucose and highly favorable sugars before switching to less-favored sources of carbon such as organic acids and alcohols. In CCR of filamentous fungi, CreA acts as a transcription factor, which is regulated to some extent by ubiquitination. CreD-HulA ubiquitination ligase complex helps in CreA ubiquitination, while CreB-CreC deubiquitination (DUB) complex removes ubiquitin from CreA, which causes its activation. CCR of fungi also involves some very crucial elements such as Hexokinases, cAMP, Protein Kinase (PKA), Ras proteins, G protein-coupled receptor (GPCR), Adenylate cyclase, RcoA and SnfA. Thorough study of molecular mechanism of CCR is important for understanding growth, conidiation, virulence and survival of filamentous fungi. This review is a comprehensive revision of the regulation of CCR in filamentous fungi as well as an updated summary of key regulators, regulation of different CCR-dependent mechanisms and its impact on various physical characteristics of filamentous fungi.

Keywords: CreA; cAMP; carbon catabolite repression; hexokinase; phosphorylation; sensing and signaling pathway; transport proteins; ubiquitination.

Figure 1

The PKA/Ras-cAMP Pathway in yeast. Adenylate cyclase is controlled by two G-Protein Systems in yeast. Ras1 and Ras2 need Sdc25 and cdc25 for activation. Ras Proteins are inactivated (Green) by Ira1 and Ira2. GPR1 system includes sucrose and glucose sensors Gpa2 and GPR1, which stimulate the adenylate activity. Krh1, Krh2, and Sch9 interact with the active Gpa2 (red), and seems to inhibit PKA activity by an unknown mechanism. Pde1 and Pde2 regulate cAMP concentration.

Figure 2

CCR regulation mechanism in S. cerevisiae. represents protein interaction in the nucleus, mig1 and hxk2, Ssn6-Tup1 co-repressor complex and mig1. Shows that there is no protein interaction, mig1 and hxk2, Ssn6-Tup1 co-repressor complex and mig1 and between Ssn6-Tup1 co-repressor complex and promoter gene. represents the inhibition of transcription [34,45,46,47,48]. During high glucose conditions, inactive Snf1 cannot cause phosphorylation of Mig1 and cellular movement of Mig1 is dependent on Glc7–Reg1 complex; whereas during low glucose levels Snf1 will be active and cause direct repression of Snf1, which will be unable to repress the CCR subjected genes.

Figure 3

Proposed CCR regulation mechanism in Aspergillus nidulans. Model representing interaction of CreA, CreB, CreC, CreD, HulA, ApyA, RcoA, SsnF, SnfA and Glc7-Reg1 complex in CCR. CreD along with HulA/ApyA is required in conjugating ubiquitin and CreA. ApyA forms strong protein-protein interaction with HulA than CreB [8,57]. However CreD and ApyA are both present in A. nidulans. CreB-CreC complex is required to remove ubiquitin from CreA–Ub complex so that CreA can repress CCR subjected genes. CreB helps in the removal of ubiquitin from CreA to prevent degradation of CreA by proteasome [8,78,79]. The role of RcoA and SsnF in binding with the promoters of glucose repressible genes along with CreA is still unclear [75,80]. However the deletion of RcoA and SsnF can be lethal for A. nidulans [74]. SnfA and SchA can play synergistic or overlapping role in regulating CreA derepression [31].