RNA biology and the adaptation of Cryptococcus neoformans to host temperature and stress

Abstract

Cryptococcus neoformans is an environmental fungus that can cause severe disease in humans. C. neoformans encounters a multitude of stresses within the human host to which it must adapt in order to survive and proliferate. Upon stressful changes in the external milieu, C. neoformans must reprogram its gene expression to properly respond to and combat stress in order to maintain homeostasis. Several studies have investigated the changes that occur in response to these stresses to begin to unravel the mechanisms of adaptation in this organism. Here, we review studies that have explored stress-induced changes in gene expression with a focus on host temperature adaptation. We compare global messenger RNA (mRNA) expression data compiled from several studies and identify patterns that suggest that orchestrated, transient responses occur. We also utilize the available expression data to explore the possibility of a common stress response that may contribute to cellular protection against a variety of stresses in C. neoformans. In addition, we review studies that have revealed the significance of post-transcriptional mechanisms of mRNA regulation in response to stress, and discuss how these processes may contribute to adaptation and virulence.

Figure 1. Transient changes in ribosomal protein (RP) transcripts and ER stress response transcripts during host-temperature adaptation are mediated by Ccr4

Upon a shift from 30°C to 37°C, RP transcripts are immediately repressed, at least in part, by Ccr4-dependent degradation. After one hour, maximum repression is reached and RP transcript levels recover to pre-shift abundance in the wildtype (solid blue line). In the absence of Ccr4, RP transcripts remain stable during the temperature shift and little change is observed in steady state levels (dashed blue line). Immediately following the temperature shift ER stress transcripts are induced to elicit the ER stress response (in both the wild type and the ccr4Δ mutant). Peak induction is reached after 1hr. During the second and third hours the resolution of the ER stress response is facilitated by repression of the ER stress mRNAs to pre-shift levels in the wild type (solid red line). The resolution of the ER stress response is mediated, in part, by Ccr4-dependent degradation of the ER stress mRNAs, as these transcripts remain at induced levels in the ccr4Δ mutant (dashed red line).