# Supplement to: Stress Responsive Reprogramming of Translating mRNA Pools in C. neoformans

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2024 · $41,694

## Abstract

Abstract:
The pathogenic fungus Cryptococcus neoformans continues to be the cause of 15% of AIDS-related mortality,
primarily in under-resourced areas of the globe. The work outlined in the proposal is a continuation of work
investigating post-transcriptional and translational mechanisms of stress adaptation in this important fungal
pathogen and investigate their conservation across clinical isolates from AIDS-associated cryptococcosis in
Africa. We have implicated translatome reprogramming as a requirement for the adaptation to host-
temperature stress as well as oxidative stress. This reprogramming is regulated at two points: the entry of
mRNAs into the translating pool through regulation of translation initiation, and the removal of mRNAs from the
pool by deadenylation-dependent mRNA decay. These two pathways cooperate in a stress-specific and
intensity-dependent manner to achieve a stress-adaptive translatome. In this proposal, we propose three
specific aims that outline a mechanistic investigation of these processes. First, we will investigate the
translational regulation of Gcn4, the transcription factor that controls expression of the integrated stress
response (ISR) regulon. We will define the C. neoformans ISR, and define the direct targets of Gcn4 in C.
neoformans. Second, we will build on preliminary data demonstrating that translation initiation regulation by the
kinase Gcn2 is activated by perturbations in other post-transcriptional and translation regulatory pathways
suggesting a role for Gcn2 as a failsafe responder to stress. We will investigate the contributions to
translatome reprogramming of these additional pathways, Hog1/p38, Nonsense Mediate Decay (NMD) and
Ribosome Quality Control (RQC) and investigate the role of Gcn2 activation in either suppressing or
exacerbating defects in translatome reprogramming or virulence phenotype. Finally, we will investigate the
mechanisms of translatome reprogramming in a panel of environmental C. neoformans isolates, as well as a
large collection of clinical isolates of C. neoformans from people with AIDS-associated cryptococcosis in Africa
that have accompanying outcome data and are fully genome sequenced. We will investigate the thresholds for
activation of these pathways and the intensity and duration of responses across the isolates, assessing
temperature dependent changes in translational output and both cytoplasmic and mitochondrial intracellular
reactive oxygen species as ISR activators. We will also determine if the ISR regulon differs across the panel of
clinical isolates. This work will define pathways responsible for the agility of this important pathogen that differ
from non-pathogen environmental relatives and from the model yeast and identify additional targets for future
therapeutic interventions.

## Key facts

- **NIH application ID:** 11062862
- **Project number:** 3R01AI131977-06A1S1
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** John C Panepinto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,694
- **Award type:** 3
- **Project period:** 2017-05-10 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11062862

## Citation

> US National Institutes of Health, RePORTER application 11062862, Supplement to: Stress Responsive Reprogramming of Translating mRNA Pools in C. neoformans (3R01AI131977-06A1S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11062862. Licensed CC0.

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