Insights and Perspectives on the Role of Proteostasis and Heat Shock Proteins in Fungal Infections

Abstract

Fungi are a diverse group of eukaryotic organisms that infect humans, animals, and plants. To successfully colonize their hosts, pathogenic fungi must continuously adapt to the host's unique environment, e.g., changes in temperature, pH, and nutrient availability. Appropriate protein folding, assembly, and degradation are essential for maintaining cellular homeostasis and survival under stressful conditions. Therefore, the regulation of proteostasis is crucial for fungal pathogenesis. The heat shock response (HSR) is one of the most important cellular mechanisms for maintaining proteostasis. It is activated by various stresses and regulates the activity of heat shock proteins (HSPs). As molecular chaperones, HSPs participate in the proteostatic network to control cellular protein levels by affecting their conformation, location, and degradation. In recent years, a growing body of evidence has highlighted the crucial yet understudied role of stress response circuits in fungal infections. This review explores the role of protein homeostasis and HSPs in fungal pathogenicity, including their contributions to virulence and host-pathogen interactions, as well as the concerted effects between HSPs and the main proteostasis circuits in the cell. Furthermore, we discuss perspectives in the field and the potential for targeting the components of these circuits to develop novel antifungal therapies.

Keywords: ERAD; HSPs; UPR; UPS; antifungal therapy; fungal infections; heat shock proteins; pathogenic fungi; proteostasis; stress-response.

Figure 1

Schematic representation of the processes for the maintenance of cellular proteostasis. In this overview, the unfolded protein response (UPR) (2), ubiquitin–proteasome system (UPS) (3), endoplasmic reticulum-associated degradation (ERAD) (4), and the autophagy (5) pathways are represented. These systems are activated after some stress reaches the cell (1). The UPR pathway (2) is composed of the transmembrane stress sensor Ire1/IreA (Ser/Thr kinase) and the chaperone protein commonly known as BiP (a Hsp70 family member). Under stress conditions, the central regulatory transcription factor in the UPR pathway (Hac1/HacA) is activated by Ire1/IreA. It migrates to the nucleus, regulating the expression of genes that support endoplasmic reticulum proteostasis. The chaperones calnexin and calreticulin cooperate in maintaining the quality control of ER proteins. Proteins that fail to reach their proper conformation are then targeted by mannosylation and transported to the cytoplasm for further degradation by the UPS pathway (3). Misfolded proteins coming from the cytoplasm or arriving from other cellular compartments are also targeted by ubiquitination for recognition by the proteasome and are then degraded (ERAD 4). The process of autophagy (5) also operates in association with HSPs to maintain cellular proteostasis by recycling/degrading misfolded proteins in a lysosome-dependent manner.

Figure 2

Schematic representation of sHsps function. (a) sHSPs cell localization is marked by red asterisks. (b) sHSPs organize into oligomers. (c) Oligomers act to delay of the onset of protein misfolding and aggregation. (d) sHsp30 downregulates the activity of the H+ ATPase under ATP starvation.

Figure 3

Schematic representation of Hsp60 function. (a) Hsp60 cell localization is marked by red asterisks. (b,c) Hsp60 acts together with Hsp70 to fold and transport target proteins.

Figure 4

Schematic representation of Hsp70 function. (a) Hsp70 cell localization is marked by red asterisks. (b–d) The centralized role of Hsp70 in folding, refolding, and transporting client proteins.

Figure 5

Schematic representation of Hsp40 function. (a) Hsp40 cell localization is marked by red asterisks. (b–d) Hsp40 links to Hsp70 to fold and transport numerous target proteins that participate in a wide range of cellular processes.

Figure 6

Schematic representation of Hsp90 function. (a) Hsp90 cell localization is marked by red asterisk. (b) The ability of Hsp90 to fold numerous target proteins. (c) Hsp90 binds and maintains the proper conformation of target proteins (e.g., transcription factors and protein kinases).

Figure 7

Schematic representation of Hsp104 function. (a) Hsp104 cell localization is marked by red asterisk. (b) The ability of Hsp104 to prevent protein aggregation (assisted by Hsp70 and Hsp40 directing client proteins to Hsp104). (c) The role of Hsp104 in reversing amorphous and amyloid protein aggregates.

Figure 8

Pathways and HSPs recruited for cellular proteostasis in response to stress. The functionality of the different pathways is represented. Such molecular circuits support cellular proteostasis either by monitoring the conformation of endoplasmic reticulum proteins and activating necessary transcriptional changes through the action of transcriptional factors (UPR—(D)), targeting misfolded proteins for proteasomal degradation (ERAD—(E) and UPS—(F)), or degrading and recycling proteins via autophagy by lysosomes (Autophagy—(G)). The major HSPs are also represented. Hsp70 performs a centralized role in the cell in association with other HSPs, such as Hsp40 (A) and Hsp104 (B), acting for folding, refolding, and transport functions, as well as preventing the formation of amorphous and amyloid aggregates. Hsp90 is also represented (C) and plays a critical role in stress-responsive circuits, maintaining the conformation of very specific client proteins, such as kinases and transcription factors. These mechanisms work together to ensure cellular proteostasis, enabling the adaptation and resistance of fungal pathogens under stress conditions induced by the host environment.