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mRNA decay: an adaptation tool for the environmental fungal pathogen Cryptococcus neoformans

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Fungi are ubiquitous in the environment and humans constantly encounter them in the soil, air, water, and food. The vast majority of these interactions are inconsequential. However, in the context of immunodeficiency precipitated by HIV infection, hematologic malignancy, or transplantation, a small subset of fungi can cause devastating, systemic infection. The most deadly of the opportunistic environmental fungi, Cryptococcus neoformans, is estimated to cause hundreds of thousands of deaths per year, mostly in the context of HIV co‐infection. The cellular processes that mediate adaptation to the host environment are of great interest as potential novel therapeutic targets. One such cellular process important for host adaptation is mRNA decay, which mediates the specific degradation of subsets of functionally related mRNAs in response to stressors relevant to pathogenesis, including human core body temperature, carbon limitation, and reactive oxygen stress. Thus, for C. neoformans, host adaptation requires mRNA decay to mediate rapid transcriptome remodeling in the face of stressors encountered in the host. Several nodes of stress‐responsive signaling that govern the stress‐responsive transcriptome also control the decay rate of mRNAs cleared from the ribosome during stress, suggesting an additional layer of coupling between mRNA synthesis and decay that allows C. neoformans to be a successful pathogen of humans. WIREs RNA 2017, 8:e1424. doi: 10.1002/wrna.1424 This article is categorized under: RNA Turnover and Surveillance > Regulation of RNA Stability
mRNA decay permits temperature adaptation through promoting transcriptional buffering. Ribosomal protein (RP) transcripts are removed from the transcriptome by Pkh2‐dependent acceleration of mRNA decay as stress‐response mRNAs are introduced. Likewise, mRNA decay controls the duration of the stress response, allowing RP transcripts to reenter during stress recovery. In the absence of mRNA decay, the retention of RP transcripts prevents a reprogramming of the transcriptome to be fully stress‐responsive. Likewise, loss of accelerated decay of stress‐response mRNAs prevents stress recovery. The red line represents RP transcripts and the blue line represents the stress‐responsive transcriptome.
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Transcriptome buffering by mRNA decay. Under unstressed conditions a basal level of mRNA synthesis and decay balance one another to maintain a stable transcriptome without large fluctuations in mRNA abundance. The red line represents ribosomal protein (RP) transcripts, the blue line represents the stress‐responsive transcriptome, and the broken line indicates average total transcripts.
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Mechanistic model for stress‐responsive regulation of mRNA decay. PKA (protein kinase A) and Pkh2 function to accelerate mRNA decay in response to stress, but the direct targets are unknown. Phosphorylation of the translational machinery may signal repression leading to recruitment of Ccr4 to the ribosome. Direct phosphorylation of the mRNA decay machinery may lead to increased activity or localization to target transcripts. Direct phosphorylation of other factors, such as chaperones, may signal the recruitment of the decay machinery to the ribosome. Future work is needed to determine the direct targets of Pkh2 and Hog1 phosphorylation that modulate mRNA decay, keeping in mind that each pathway may operate at unique points of regulation.
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Hog1 (high osmolarity glycerol) and PKA (protein kinase A) control separate aspects of adaptation to changes in carbon availability. Hog1 controls the decay of ribosomal protein (RP) transcript upon starvation, whereas PKA controls the stabilization and potentiation of RP transcripts during glucose refeeding. The red line represents RP transcripts.
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During starvation, the transcriptome is not buffered, but is repressed significantly through mRNA decay. During glucose refeeding, synthesis and stabilization potentiate the reintroduction of ribosomal protein (RP) transcripts and restoration of transcriptome homeostasis. In the absence of mRNA decay the logarithmic decay of RP transcripts is attenuated to a linear decay, delaying the repression of the transcriptome. The red line represents RP transcripts.
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