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Chaperone Networks in Fungal Pathogens of Humans Journal of Fungi Review Chaperone Networks in Fungal Pathogens of Humans Linda C. Horianopoulos and James W. Kronstad * Michael Smith Laboratories, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; [email protected] * Correspondence: [email protected] Abstract: The heat shock proteins (HSPs) function as chaperones to facilitate proper folding and mod- ification of proteins and are of particular importance when organisms are subjected to unfavourable conditions. The human fungal pathogens are subjected to such conditions within the context of infection as they are exposed to human body temperature as well as the host immune response. Herein, the roles of the major classes of HSPs are briefly reviewed and their known contributions in human fungal pathogens are described with a focus on Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. The Hsp90s and Hsp70s in human fungal pathogens broadly contribute to thermotolerance, morphological changes required for virulence, and tolerance to antifungal drugs. There are also examples of J domain co-chaperones and small HSPs influencing the elaboration of virulence factors in human fungal pathogens. However, there are diverse members in these groups of chaperones and there is still much to be uncovered about their contributions to pathogenesis. These HSPs do not act in isolation, but rather they form a network with one another. Interactions between chaperones define their specific roles and enhance their protein folding capabilities. Recent efforts to characterize these HSP networks in human fungal pathogens have revealed that there are unique interactions relevant to these pathogens, particularly under stress conditions. The chaperone networks in the fungal pathogens are also emerging as key coordinators of pathogenesis and antifun- gal drug tolerance, suggesting that their disruption is a promising strategy for the development of Citation: Horianopoulos, L.C.; antifungal therapy. Kronstad, J.W. Chaperone Networks in Fungal Pathogens of Humans. J. Keywords: heat shock proteins; chaperones; fungal pathogens; thermotolerance; antifungal drug tolerance Fungi 2021, 7, 209. https://doi.org/ 10.3390/jof7030209 Academic Editor: David S. Perlin 1. Introduction Human fungal pathogens must be able to survive and proliferate in the host envi- Received: 6 February 2021 ronment despite several unfavourable conditions. A major barrier to systemic infections Accepted: 10 March 2021 Published: 12 March 2021 in humans is the elevated mammalian body temperature compared to the ambient en- vironment [1]. Human body temperature effectively restricts the growth of most fungi Publisher’s Note: MDPI stays neutral and, indeed, the majority of fungal infections are superficial and occur on the skin where with regard to jurisdictional claims in temperatures are less restrictive [2,3]. Several human fungal pathogens also undergo published maps and institutional affil- morphological changes such as the transition between yeast and hyphae in response to iations. temperature differences [4]. In order to survive at core human body temperature and to undergo these morphological changes, fungi must be able to cope with the proteotoxic stress induced at high temperature and upon flux in the demand for protein production. The heat shock proteins (HSPs) are one of the major groups of proteins which help respond to and mitigate these stresses. Herein, we will describe the general roles and classifications Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. of HSPs, their known roles in the major human fungal pathogens, and the interactions This article is an open access article between HSPs which coordinate chaperoning activity. distributed under the terms and Classically, HSPs are defined as those proteins that are upregulated upon temperature conditions of the Creative Commons upshift and stress induction as well as those which share a high degree of sequence simi- Attribution (CC BY) license (https:// larity to established categories of HSPs [5]. Despite the general property of upregulation creativecommons.org/licenses/by/ under stress conditions, there are also examples of HSPs that are constitutively expressed. 4.0/). Therefore, it is speculated that these proteins may have evolved to fulfill a proactive role J. Fungi 2021, 7, 209. https://doi.org/10.3390/jof7030209 https://www.mdpi.com/journal/jof J. Fungi 2021, 7, x FOR PEER REVIEW 2 of 16 upregulation under stress conditions, there are also examples of HSPs that are constitu- J. Fungi 2021, 7, 209 tively expressed. Therefore, it is speculated that these proteins may have evolved to2 fulfill of 15 a proactive role of ensuring proper folding of nascent proteins and thus preventing the accumulation of proteotoxic stress rather than as a mechanism to respond to stresses such of ensuring proper folding of nascent proteins and thus preventing the accumulation of as heat shock [6]. The HSPs are involved in multiple processes including folding proteins proteotoxic stress rather than as a mechanism to respond to stresses such as heat shock [6]. de novo, stabilizing protein conformation under stress conditions, and modulating pro- The HSPs are involved in multiple processes including folding proteins de novo, stabilizing tein conformation to regulate their activity [7]. This modulation can involve individual protein conformation under stress conditions, and modulating protein conformation to regulateproteins their or multiprotein activity [7]. Thiscomplexes modulation which can must involve be assembled individual or proteins disassembled or multiprotein for their complexesfunction [8] which. must be assembled or disassembled for their function [8]. HSPsHSPs havehave typicallytypically beenbeen namednamed basedbased onon their their sizes sizes and and classified classified based based on on their their sequencesequence similarity. similarity. This This often often reflects reflects how how they they function, function, but but provides provides limited limited informa- infor- tionmation about about their their clients clients or theor the pathways pathways in whichin which they they participate. participate. In In general, general, there there are are ATP-dependentATP-dependent HSPs HSPs including including Hsp90, Hsp90, Hsp70, Hsp70, chaperonins, chaperonins and, and disaggregases disaggregases which which un- dergoundergo conformational conformational changes changes upon upon ATP ATP hydrolysis hydrolysis to facilitate to facilitate protein protein folding, folding, complex com- assembly,plex assembly, or disaggregation. or disaggregation. There There are also are energy-independent also energy-independent passive passive chaperones chaperones such assuch the as small the HSPssmall whichHSPs normallywhich normally act as holdasesact as holdases to prevent to prevent protein protein aggregation. aggregation There . areThere also are many also co-chaperones many co-chaperones required required to recruit to clients recruit as clients well as as to well facilitate as to thefacilitate ATPase the activityATPase of activity their chaperones; of their chaperones however,; we however will focus, we on will the focus Hsp40/J-domain on the Hsp40/J co-chaperones-domain co- ofchaperones Hsp70s as of they Hsp70s share as a they highly share conserved a highly domain conserved and domain have emerging and have importance emerging im- in fungalportance pathogens. in fungal These pathogens. energy-dependent These energy and-dependent -independent and - chaperonesindependent as chaperone well as theirs as co-chaperoneswell as their coordinatelyco-chaperones ensure coordinately that cells canensure function that incells normal can function and stressed in normal conditions and includingstressed conditions those relevant including to proliferation those relevant in a humanto proliferation host. The in major a human classes host. of HSPsThe major are reviewedclasses of below HSPs are with reviewed descriptions below of with their descriptions major reported of their functions major inreported the model functions species in Saccharomycesthe model species cerevisiae Saccharomycesto provide context,cerevisiae as to well provide as current context, information as well as on current their known infor- rolesmation in theon majortheir known human roles fungal in the pathogens major human (Figure fungal1). pathogens (Figure 1). Figure 1. The major roles of heat shock proteins (HSPs) in fungal pathogens. The HSPs facilitate Figure 1. The major roles of heat shock proteins (HSPs) in fungal pathogens. The HSPs facilitate the the acquisition of thermotolerance and allow human fungal pathogens to grow at human body acquisition of thermotolerance and allow human fungal pathogens to grow at human body temper- temperature as well as to survive after heat shock at elevated temperatures. Several of these chap- atureerones as are well required as to survive for morphological after heat shock changes at elevated including temperatures. the yeast to Severalhyphal transition of these chaperones and conidi- areation. required The HSPs, for morphological and in particular changes the Hsp90s, including also thefacilitate yeast toantifungal hyphal transitiondrug tolerance and conidiation.in the major Thefungal HSPs, pathogens and in particular suggesting the that Hsp90s, inhibitors also facilitatewould potentiate antifungal the drug activities tolerance of existing in the major antifungals. fungal pathogensFinally, in suggestingmammalian
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