The fate of misfolded glycoproteins in filamentous fungi

The majority of fungal species cause relatively harmless infections in humans, but under special circumstances can be severe leading even to death. Fungal infections have one of the highest mortality rates, while some patients with COVID19 could also show an increased susceptibility to those. Development of resistant fungal strains against widely-used antifungal compounds is an emerging problem, and the need for new antifungal drugs is imminent. Since fungi are eukaryotic organisms, similar to the human ones, discovery of new drug targets is challenging due to serious side effects.

Secreted proteins play an important role in fungal infection process. In order to be fully functional, proteins need to be modified. One of the most common modification is the attachment of a sugar chain to the protein (N-glycosylation), which plays a crucial role in correct folding and function. However, misfolded proteins can be formed and cells must cope with this stress. Different mechanisms can be deployed by cells to degrade misfolded glycoproteins.

Deglycosylation, the removal of the sugar chain, is a crucial initial step for further protein degradation. These mechanisms can create side products such as free sugar chains (N-glycans) that also must be degraded by specialized deglycosylating enzymes. Our previous preliminary data showed that fungi possibly utilize different mechanisms as compared to mammalian cells to cope with this stress.

We also found that deletion of deglycosylating enzymes had a severe phenotypic impact and reduced the amount of secreted proteins, indicating that this process could affect the fungal virulence as well.

The overall aim of my research is to investigate the strategies, filamentous fungi deploy in order to cope with stress caused by accumulation of misfolded N-glycoproteins and the role of free N-glycans in fungal infection process. This research will give valuable information regarding the role of deglycosylation of misfolded N-glycoproteins and the fate of free N-glycans in filamentous fungi biology, contributing to better understanding of the mechanisms fungi deploy to cope with this stress. The outcome of my research could contribute to the development of new therapeutic strategies to control fungal diseases, reducing the risk of antifungal resistance.