Endoplasmic reticulum stress and fungal pathogenesis

Abstract

The gateway to the secretory pathway is the endoplasmic reticulum (ER), an organelle that is responsible for the accurate folding, post-translational modification and final assembly of up to a third of the cellular proteome. When secretion levels are high, errors in protein biogenesis can lead to the accumulation of abnormally folded proteins, which threaten ER homeostasis. The unfolded protein response (UPR) is an adaptive signaling pathway that counters a buildup in misfolded and unfolded proteins by increasing the expression of genes that support ER protein folding capacity. Fungi, like other eukaryotic cells that are specialized for secretion, rely upon the UPR to buffer ER stress caused by fluctuations in secretory demand. However, emerging evidence is also implicating the UPR as a central regulator of fungal pathogenesis. In this review, we discuss how diverse fungal pathogens have adapted ER stress response pathways to support the expression of virulence-related traits that are necessary in the host environment.

HacA Governs Virulence Traits and Adaptive Stress Responses in Trichophyton rubrum

“…Endoplasmic reticulum (ER) is the gateway for the secretory pathway and is the center for post-translational modification, accurate folding, and assembly of up to 30% of the cellular proteome (Schwarz and Blower, 2016). Fungi are organisms specialized for secretion and the utilization of this mechanism is entwined to the ability to sense environmental stress, thus leading to adequate responses (Krishnan and Askew, 2014). As homeostasis in the ER secretory capacity is followed by UPR activation, and current research has reported that the UPR genes are important vulnerability points to be exploited in fungal therapy, we decided to address the scope of hacA in the dermatophyte T. rubrum.…”

“…The endoplasmic reticulum (ER) represents the gateway of the secretory pathway, where most of the plasma membrane and secreted proteins undergo proper folding and posttranslation modifications (Schwarz and Blower, 2016). The secretory system is used by different pathogens to express virulence factors, and to cope with stress conditions, which ultimately might favor their adaptation to specific biological niches (Krishnan and Askew, 2014).…”

“…It is assumed to be an essential regulator of Aspergillus fumigatus pathogenicity Richie et al, 2011). Moreover, in Cryptococcus neoformans and Candida albicans, UPR affected virulence traits as deletions in these genes were associated with impairment of the ability to switch from yeast to hyphal form, compromised cell wall adhesive proteins, and reduction of thermotolerance (Matsumoto et al, 2005;Wimalasena et al, 2008;Blankenship et al, 2010;Krishnan and Askew, 2014).…”

“…Notably, consistent divergences of domain structure from mammalian Hac1/HacA ortholog, termed Xbp1, denote HacA as an attractive target for antifungal therapy (Zhang et al, 2016). Further, the current paradigm is that ER-stress response pathways are involved in the expression of different virulence traits that may be necessary for pathogen-host interaction (Krishnan and Askew, 2014). Thus, we have addressed the scope of HacA in the dermatophyte Trichophyton rubrum.…”

Hansenula polymorpha Hac1p Is Critical to Protein N -Glycosylation Activity Modulation, as Revealed by Functional and Transcriptomic Analyses

“…Moreover, recent studies strongly implicate UPR as a central regulator of fungal pathogenesis (26). The basic features of the Hac1-dependent UPR signaling pathway appear to be well conserved in most fungal species, although several recent reports have revealed unexpected variations, such as the lack of the Hac1 homolog in the fission yeast Schizosaccharomyces pombe (27) and the absence of the canonical Ire1-Hac1 UPR in Candida glabrata (28).…”