Detalle de: Multi-omic data and modelling analyses reveal that HAP complex integrates TORC1/PKA and SNF1 signalling pathways

Crabtree-positive yeast species such as Saccharomyces cerevisiae produce most of their ATP through alcoholic fermentation in the presence of oxygen and abundant glucose. This seemingly inefficient growth strategy leads to substantial industrial losses. Thus, many research efforts have focused on formulating hypotheses and computational growth models to explain this phenomenon, but have not given much attention to the development of dynamic models that integrate growth and mechanistic regulation of protein expression. From a regulatory point of view, this phenotype implies rapid growth and repression of respiratory genes. When intracellular glucose levels are low, SNF1 and the HAP complex control respiration activation. Among the proteins in the HAP complex, only HAP4 is believed not to be constitutively expressed and is considered the signal transduction element in this pathway. The transcription of genes from the translation machinery is primarily associated with TORC1 and PKA. Here, we have formulated an integrated dynamic model of respiro-fermentative growth and regulation of S. cerevisiae using two proteomic data sets obtained during diauxic shift experiments. After analysing the model and data, we concluded that HAP5 is also up-regulated in response to decreasing glucose levels, and this regulation occurs downstream of the TORC1 and PKA pathways. These two hypotheses were validated using independent transcriptomics data sets. Given its architecture, we postulate that the HAP complex integrates information from the PKA/TORC1 and SNF1 pathways. Our findings provide valuable information on the evolution of the Crabtree effect and can help design strategies to reduce its impact.