Cross-Kingdom Control: Yeast Prion Protein [MRPL10+] Modulates Host Physiology in Drosophila
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eLife Assessment
This valuable study shows first that yeast strains potentially associated with the [MRPL10+] prion state strongly influence Drosophila cold tolerance and locomotor behavior, and it goes on to exploit natural variation to identify host pathways contributing to these responses. The evidence for host physiology and genetics is solid, but the evidence for MRPL10 prion causality is incomplete because the prion state has not been directly validated in the yeast strains used. The study would be substantially strengthened either by establishing the presence of the MRPL10 prion state, or by tempering the prion-specific causal claims and framing involvement of MPRL10 or other prions in the yeast strains as a plausible but unproven mechanism. The work will be of interest to many fields, including quantitative genetics, insect physiology and microbe-host interactions.
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Abstract
Prions, once mainly studied for their pathogenic roles, are now gaining recognition as adaptive elements in microbial physiology. Over one-third of wild yeast isolates harbor prion proteins, yet their impact on host-microbe interactions remains poorly characterized. Given the ecological dominance of yeasts in the Drosophila mycobiome, we leveraged the Drosophila melanogaster—Saccharomyces cerevisiae system to investigate how the mycobiome-derived prion, [MRPL10+], modulates host physiology. We show that flies exposed to [MRPL10+] yeast exhibit significantly enhanced cold tolerance and increased locomotor activity. This effect persists with heat-killed yeast and diluted culture, suggesting a stable, potent bioactive factor. Using the genetically diverse Drosophila Global Diversity Lines (GDL), we identified natural variation in responsiveness to [MRPL10+] yeast. Genome-wide association and functional RNAi screening revealed a gut-brain signaling axis involving genes critical for digestion, intercellular communication, transcription regulation, and neural transmission. Notably, serotonin and octopamine pathways were essential for [MRPL10+]-induced changes in cold tolerance and locomotion, implicating neuromodulatory circuits in prion-mediated microbial signaling. Our findings establish a mechanistic link between a fungal prion and host metabolic and neural adaptation. This work provides the first genetic dissection of a prion-mediated host-microbe interaction, laying the groundwork for investigating beneficial prions in complex microbial communities and highlighting a new dimension of the mycobiome’s influence on animal physiology.
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eLife Assessment
This valuable study shows first that yeast strains potentially associated with the [MRPL10+] prion state strongly influence Drosophila cold tolerance and locomotor behavior, and it goes on to exploit natural variation to identify host pathways contributing to these responses. The evidence for host physiology and genetics is solid, but the evidence for MRPL10 prion causality is incomplete because the prion state has not been directly validated in the yeast strains used. The study would be substantially strengthened either by establishing the presence of the MRPL10 prion state, or by tempering the prion-specific causal claims and framing involvement of MPRL10 or other prions in the yeast strains as a plausible but unproven mechanism. The work will be of interest to many fields, including quantitative genetics, insect …
eLife Assessment
This valuable study shows first that yeast strains potentially associated with the [MRPL10+] prion state strongly influence Drosophila cold tolerance and locomotor behavior, and it goes on to exploit natural variation to identify host pathways contributing to these responses. The evidence for host physiology and genetics is solid, but the evidence for MRPL10 prion causality is incomplete because the prion state has not been directly validated in the yeast strains used. The study would be substantially strengthened either by establishing the presence of the MRPL10 prion state, or by tempering the prion-specific causal claims and framing involvement of MPRL10 or other prions in the yeast strains as a plausible but unproven mechanism. The work will be of interest to many fields, including quantitative genetics, insect physiology and microbe-host interactions.
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Reviewer #1 (Public review):
This manuscript by Lin et al. was a pleasure to read, and the results were quite surprising. The first surprise was the strength of the effects of the [MRPL10+] yeast prion on Drosophila locomotory behavior and chill recovery. The second was that this effect is highly polymorphic in different Drosophila lines, allowing the authors to perform a GWAS and implicate a number of genes involved in gut-brain signaling, thereby establishing a clear mechanism for this effect. The third was that many of these GWAS hits were validated by RNAi, giving further support to their involvement. I only have a few minor questions.
(1) Does the evidence really "support a model in which [MRPL10+] yeast promotes cold tolerance by activating serotonin signaling while simultaneously suppressing octopaminergic signaling"? I agree …
Reviewer #1 (Public review):
This manuscript by Lin et al. was a pleasure to read, and the results were quite surprising. The first surprise was the strength of the effects of the [MRPL10+] yeast prion on Drosophila locomotory behavior and chill recovery. The second was that this effect is highly polymorphic in different Drosophila lines, allowing the authors to perform a GWAS and implicate a number of genes involved in gut-brain signaling, thereby establishing a clear mechanism for this effect. The third was that many of these GWAS hits were validated by RNAi, giving further support to their involvement. I only have a few minor questions.
(1) Does the evidence really "support a model in which [MRPL10+] yeast promotes cold tolerance by activating serotonin signaling while simultaneously suppressing octopaminergic signaling"? I agree about serotonin, but the role of octopamine seems less clear. Figure 3d shows that mutants for genes involved in octopamine synthesis (Tdh2) and a receptor (Octβ2R) have higher cold tolerance, irrespective of [MRPL10+]. So while this does establish a role for these two genes in cold tolerance, what is the evidence that [MRPL10+] suppresses octopaminergic signaling? These seem to be two different questions. In other words, maybe any mutant with increased cold tolerance would show no response to [MRPL10+], regardless of whether the mutated gene is involved in mediating [MRPL10+]'s effects.
(2) I was also somewhat confused by the results of Supplementary Figure 4. In S4a, inhibition of octopaminergic neurons (TDC2 > TNT) seems to decrease locomotory behavior in response to [MRPL10+], which is the opposite of what I would expect from the cold tolerance experiments in Figure 3d. And then in the S4c legend, it is stated that "Loss of the octopamine biosynthesis gene Tdc2 or its receptors Octβ2R and Octβ3R triggers elevated locomotor activity even in flies fed wild-type yeast, mimicking the [MRPL10+] phenotype." I can see this for the two receptors, where both the red and black lines show high locomotor activity (>1000 passes) near the middle of each 24-hour experiment, but the Tdc2 graph in S4c looks quite different, with the [MRPL10+] activity never going above ~200 passes at any time point and the wt activity showing high variability. So if I understand the data correctly, it seems that Tdc2 mutants have higher cold tolerance (Figure 3d) but not higher locomotory behavior (Figure S4c).
(3) To summarize, I don't see how the data in either Figure 3d or Supplementary Figure 4 support a role of octopamine in the [MRPL10+] mechanism. Even in cases where perturbing a gene/neuron type abolishes the effects of [MRPL10+] on locomotory behavior or cold tolerance, this establishes a role for them in locomotory behavior or cold tolerance, but not for mediating [MRPL10+]'s effects (for the same reason given in #1 above). In contrast, the 5-HT2A results in Figure 3d do establish mechanistic relevance for serotonin, since the mutant affects only the response to [MRPL10+], but not wt.
(4) Finally, I am intrigued by the idea at the end of the paper that this represents a symbiotic adaptation. Have [MRPL10+] yeast ever been found in the wild? If not, perhaps its effects on flies are unlikely to represent anything adaptive? And if the prion is present in the wild, I wonder: if it's to a fly's advantage to have higher cold tolerance or locomotory behavior, why couldn't it evolve that itself, without needing a prion to induce it? Given the incredible adaptability of flies, I would guess that any physiological effects of a yeast prion would more likely push a fly away from its fitness optimum, and only benefit the yeast-- for example, by increasing yeast dispersal at the cost of a fly's fecundity. The main exception to that would be if [MRPL10+] yeast were only present in some specific environments that the flies couldn't adapt to on their own, but that seems unlikely.
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Reviewer #2 (Public review):
Summary:
In this manuscript, the authors report on how a prion protein originating in yeast inside the gut interacts with a host insect's physiology to influence organismal traits important to fitness. Other recent studies have strongly found that interactions between gut yeasts and their Drosophila hosts are important to feeding behaviour, growth performance, and cold tolerance. They even point to the gut-brain axis. The authors extended from this work, combining screening approaches, genome-wide association studies, and forward genetics to determine that octopamine and serotonin signalling are important to these effects.
Strengths:
The data represent a valuable addition to the literature. There is a growing appreciation that host-microbiome interactions are important to animal performance and fitness, and …
Reviewer #2 (Public review):
Summary:
In this manuscript, the authors report on how a prion protein originating in yeast inside the gut interacts with a host insect's physiology to influence organismal traits important to fitness. Other recent studies have strongly found that interactions between gut yeasts and their Drosophila hosts are important to feeding behaviour, growth performance, and cold tolerance. They even point to the gut-brain axis. The authors extended from this work, combining screening approaches, genome-wide association studies, and forward genetics to determine that octopamine and serotonin signalling are important to these effects.
Strengths:
The data represent a valuable addition to the literature. There is a growing appreciation that host-microbiome interactions are important to animal performance and fitness, and this work provides strong evidence for a causal role of a prion protein in such a relationship. The high-throughput screening approaches and sequencing were, to the best of my knowledge, completed correctly. The idea that prion proteins could influence host physiology in beneficial ways is compelling, and the authors have done a great job of walking the reader through their reasoning and the multiple lines of evidence that support their reasoning.
Weaknesses:
While this is an interesting topic that is worthy of investigation, and identifying a causal role for a prion protein in host effects is a significant advance, other aspects of the novelty of the work are strongly overstated. No clear justification is provided for why cold tolerance was a particular trait of interest in the present study. Yet, a recent publication in the Journal of Experimental Biology clearly demonstrated a role of gut yeasts in Drosophila cold tolerance and is not cited or otherwise acknowledged [see: Jiménez-Padilla and Sinclair. Gut yeasts accelerate chill coma recovery in Drosophila melanogaster. J Exp Biol (2026) 229 (9): jeb251533]. I trust this is an oversight and will be corrected. Integrating this knowledge into the narrative of the paper would strongly improve the reasoning for this study.
The authors rely on a review of chill coma mechanisms from 2011 as their primary source of information for interpreting their results in relation to insect cold tolerance. A great deal of work has been done by several research groups on the physiology of cold tolerance in chill-susceptible insects in the past 15 years, much of which has relied on Drosophila as a model system. I think this is important and could inform the conclusions being reached and future work that extends from this work. For example, it is now well established that the renal system is centrally important to insect cold tolerance, including chill coma recovery phenotypes, but this is not being acknowledged or integrated into the narrative here and should be. Many of the mechanisms of interest highlighted in the present work are also directly relevant to other ionoregulatory epithelia beyond nervous tissue, and global knockdowns using the UAS/Gal4 approach will impact all tissues in which these genes are expressed. Figure 2D shows how these genes are enriched in the CNS, but also the midgut and Malpighian tubules, two ionoregulatory organs of import to cold tolerance.
The method the authors used to assess cold tolerance is not typically preferred by researchers who commonly study these phenotypes. Holding flies continuously at 4-6{degree sign}C and assessing whether or not they remain active is a reasonable approach, and I am confident that the differences observed among groups are real. However, chill coma onset and recovery are thought to be mediated by a complex combination of temperature effects on nervous, muscle, and renal function, and this assay method may conflate chill coma resistance with the capacity for chill coma recovery. This means variation in this assay could arise from differences in initial CTmin, plasticity in CTmin induced by RCH before chill coma is induced, or plasticity in neurumuscular/renal function that allows for recovery during the assay. I say this in part because Drosophila are documented to enter chill coma and then recover while the assay is ongoing, particularly around temperatures close to the CTmin [see: MacMillan et al., The capacity to maintain ion and water homeostasis underlies interspecific variation in Drosophila cold tolerance. Sci. Rep. 5:18607]. Therefore, flies active after 2 hours may never have entered chill coma, or may have entered and then recovered. Serotonin and octopamine signalling may be critical to one or both of these possibilities, and maybe in different ways, especially because these hormones play critically important roles in both renal and nervous function.
Infectious prions are known to cross gut epithelia and the Drosophila gut is known to take up large organic molecules via endocytosis and exocytosis, so I am not entirely convinced that the effects observed necessarily result through the gut-brain axis. Future studies could be focused on observing whether these prion proteins remain in the gut, or act directly on other tissues via the hemolymph.
The CAFÉ assay used in the study is a tried and true way to measure feeding behaviour in Drosophila. The data in Figure 1H look like a single measurement per individual, unless they have been modified for presentation. From the text provided, it is not clear to me how the authors accounted for changes in feeding behaviour at different times of day. Feeding behaviour is regulated by the circadian rhythm in digestive tissues. If activity is enhanced at night, as in the present study, are MRPL10+ flies also feeding during the night more than the WT flies?
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Reviewer #3 (Public review):
Summary:
This manuscript shows how a change in food source can lead to organismal adaptation to stress. Namely, different yeast strains impact the response of Drosophila to cold stress. An intriguing connection between food intake, gut, and neuronal signaling is described.
Strengths:
The genetic association studies suggest how pathways can be altered to provide cold tolerance in Drosophila.
Weaknesses:
[MRPL10+] is described here as a yeast prion, yet there is no solid evidence supporting this. It is unclear whether the prion exists; therefore, the primary conclusion is unclear. More biochemical analyses and additional characterization are needed to support the idea that MRPL10 is, in fact, in a prion state in the strains the authors received and utilized in this manuscript. It is unclear whether the mating …
Reviewer #3 (Public review):
Summary:
This manuscript shows how a change in food source can lead to organismal adaptation to stress. Namely, different yeast strains impact the response of Drosophila to cold stress. An intriguing connection between food intake, gut, and neuronal signaling is described.
Strengths:
The genetic association studies suggest how pathways can be altered to provide cold tolerance in Drosophila.
Weaknesses:
[MRPL10+] is described here as a yeast prion, yet there is no solid evidence supporting this. It is unclear whether the prion exists; therefore, the primary conclusion is unclear. More biochemical analyses and additional characterization are needed to support the idea that MRPL10 is, in fact, in a prion state in the strains the authors received and utilized in this manuscript. It is unclear whether the mating scheme to produce daughter cells without the prion would actually work as described, and no follow-up work verifies the lack of the prion state. In addition, more common prions were omitted from the study, and it is unclear whether they might be present in the strains used as well. There is no [PSI+], [RNQ+], or [URE3] strain assessed, and it is possible that there is another prion in the [MRPL10+] strain.
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The authors included RRIDs in their in bioRxiv paper! RRIDs improve reproducibility in scientific research. #reproducibility #ReproducibleResearch #BetterScience
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Cross-Kingdom Control: Yeast Prion Protein Modulates Host Physiology in Drosophila #NeuroDegeneration 🧪🧠 https://www.biorxiv.org/content/10.64898/2026.08.26.747210v1
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Cross-Kingdom Control: Yeast Prion Protein [MRPL10+] Modulates Host Physiology in Drosophila https://www.biorxiv.org/content/10.64898/2026.08.26.747210v1
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Cross-Kingdom Control: Yeast Prion Protein [MRPL10+] Modulates Host Physiology in Drosophila https://www.biorxiv.org/content/10.64898/2026.08.26.747210v1
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