Biology subjects

Deal, A.

Publications and source records attributed to Deal, A..

5 recordsLinked to original sources

bioRxiv2026

Evolutionary insights into an ancient fungal transition from land to sea

Though fungi have largely been studied in the context of terrestrial niches, aquatic species that originated from terrestrial ancestors can be found across the fungal kingdom. To date, the mechanisms of these transitions from land to sea have remained poorly understood, and it is unclear what traits are associated with the specialization of a fungal to marine environments. Here we develop Kluyveromyces budding yeasts, sampled from terrestrial, estuarine, and marine niches, as a model for the evolution of fungi into the ocean. Comparative analyses of genomes from the genus revealed a contraction in genome size and gene number in aquatic Kluyveromyces compared to their terrestrial relatives, including at genes annotated in alcoholic fermentation. In laboratory culture, we uncovered evidence for phenotypic losses in aquatic Kluyveromyces species, namely compromised desiccation and cold resistance relative to the terrestrial clade. Aquatic Kluyveromyces also exhibited better salt tolerance than terrestrial species, reflecting an evolutionary gain consonant with their provenance from seawater. Furthermore, in molecular-evolution analyses, we found robust signal for positive selection in the aquatic Kluyveromyces lineage, most notably at genes annotated in respiration. We interpret these results under a model in which the release of ethanol, which allows yeasts in terrestrial niches to kill off bacterial competitors at close range, has little use in the water; aquatic Kluyveromyces thus evolved to lose fermentation but gained other metabolic and stress-tolerance innovations essential for fitness in the marine niche. We propose that the syndrome of genomic features and phenotypes in aquatic Kluyveromyces reflects broadly relevant mechanisms of evolutionary transitions by fungi into ocean environments.

evolutionary biology↗

bioRxiv2026

Stereoselective methyl-swapping demonstrates target specificity of cognitive enhancer

The Integrated Stress Response (ISR) couples cellular stress sensing to translational control, playing a critical role in the homeostatic regulation of cell health. However, prolonged and unmitigated ISR activation becomes maladaptive and drives the progression of a wide range of pathologies, including cognitive decline. Pharmacological inhibition of the ISR with the small, drug-like molecule ISRIB has proven remarkably effective in reversing cognitive deficits and pathology in animal models, highlighting its potential for therapeutic intervention in humans. We engineered an allele-specific ISRIB analog (mISRIB) that selectively targets a mutant form of eIF2B, the molecular target of ISRIB, without affecting wild-type eIF2B. Notably, mISRIB treatment in mice homozygous for the eIF2B mutant allele enhances synaptic plasticity and long-term memory, confirming the on-target mechanism underlying ISRIBs cognitive benefits. Our results provide a framework for dissecting the ISRs contributions within complex cellular networks, such as those governing brain function, with precise temporal and spatial resolution.

biochemistry↗

bioRxiv2025

Allosteric Disordering of eIF2B Regulates the Integrated Stress Response

The ternary complex (TC), composed of translation initiation factor eIF2, GTP, and initiator methionyl tRNA, delivers the first amino acid to the ribosome to initiate protein synthesis. The activity of the decameric eukaryotic initiation factor 2B complex (eIF2B) initiates TC assembly by catalyzing GDP to GTP exchange on eIF2, thereby setting the TC levels in the cell. Stress-induced phosphorylation converts eIF2 from the substrate of the GDP/GTP exchange reaction into an inhibitor (eIF2-P) of eIF2B. This conversion reduces the cells TC levels and induces the widespread reprogramming of translation known as the Integrated Stress Response (ISR). Here, we chart an allosteric axis running through eIF2B, revealing the importance of a protrusive -helix in its {beta}-subunit, the latch-helix, that locks onto the -subunit to induce eIF2B activity. eIF2-P binding unhooks the latch-helix, opening eIF2B, which inhibits its GDP/GTP exchange activity. Distinct viral proteins have convergently evolved to bind to eIF2B and stabilize the latch-helix-bound active state. Using these insights, we generated ISR-ACTivating compounds, ISRACTs, that stabilize eIF2B in its inhibited, unlatched state. Our study thus highlights how state-transitions in eIF2B are regulated via long-range allostery.

biochemistry↗

bioRxiv2022

A central helical fulcrum in eIF2B coordinates allosteric regulation of Integrated Stress Response signaling

The Integrated Stress Response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR underlies age-related diseases. ISR signaling down-regulates translation and activates expression of stress-responsive factors that promote return to homeostasis, and is initiated by inhibition of the decameric guanine nucleotide exchange factor eIF2B. Conformational and assembly transitions regulate eIF2B activity, but the allosteric mechanisms controlling these dynamic transitions are unknown. Using hydrogen deuterium exchange-mass spectrometry and cryo-EM, we identified a single alpha-helix whose orientation allosterically controls eIF2B conformation and assembly. Biochemical and signaling assays show that this "Switch-Helix" controls eIF2B activity and signaling in cells. In sum, the Switch-Helix acts as a fulcrum of eIF2B conformational regulation and is a highly conserved actuator of ISR signal transduction. This work uncovers a novel allosteric mechanism and unlocks new therapeutic possibilities for ISR-linked diseases.

biochemistry↗

bioRxiv2022

Keratinocyte-Associated Protein 3 is a novel gene for adiposity with differential effects in males and females

ObjectiveDespite the obesity crisis in the United States, the underlying genetics are poorly understood. Our lab previously identified Keratinocyte-associated protein 3, Krtcap3, as a candidate gene for adiposity where increased expression of Krtcap3 correlated with decreased fat mass. Here we seek to confirm that Krtcap3 expression affects adiposity traits. MethodsWe developed an in vivo whole-body Krtcap3 knock-out (KO) rat model. Wild-type (WT) and KO rats were placed onto a high-fat or low-fat diet at six weeks of age and were maintained on diet for 13 weeks, followed by assessments of metabolic health. We hypothesized that Krtcap3-KO rats will have increased adiposity and a worsened metabolic phenotype relative to WT. ResultsWe found that KO male and female rats have significantly increased body weight versus WT. KO females ate more, had more fat mass, but were also more insulin sensitive than WT. Alternatively, KO males weighed more and were more insulin resistant than WT, with no differences in eating or fat mass. ConclusionsThis study validates Krtcap3 in body weight regulation and demonstrates sex-specific effects on food intake, adiposity, and insulin sensitivity. Future studies will investigate how Krtcap3 is acting and seek to better understand these sex differences. Study Importance QuestionsWhat is already known about this subject? O_LIOver 900 low-risk, common genetic variants for BMI have been identified, but these still only explain a fraction of the heritability and many of the underlying causal genes remain unknown C_LIO_LIKrtcap3 has been identified as a candidate gene for obesity in both rats and humans, but no verification or functional studies have been done C_LI What are the new findings in your manuscript? O_LIIdentified Krtcap3 as a novel gene that impacts feeding behavior and adiposity in female rats C_LIO_LIDetermined that Krtcap3 impacts insulin sensitivity differentially in male and female rats C_LI How might your results change the direction of research or the focus of clinical practice? O_LIThis work may lead to identification of new pathways that contribute to obesity without metabolic complications, which will advance understanding of the biology of obesity and potentially identify novel drug targets C_LIO_LIThis work highlights the need to investigate sex differences in the genetics of obesity C_LI

genetics↗