Biology subjects

Verma, K.

Publications and source records attributed to Verma, K..

17 recordsLinked to original sources

bioRxiv2026

Pharmacological modulation of ATP-binding cassette transporters alters feeding phases of the sugarcane aphid on susceptible sorghum

BACKGROUND: Aphids damage crops through sustained feeding and by rapid transmission of plant viruses, processes that are not effectively prevented by conventional insecticides. The sugarcane aphid (Melanaphis sacchari), an invasive pest of sorghum in the United States, can inoculate non-persistent viruses within minutes of probing. Disrupting feeding phases represents an alternative strategy in plant disease and integrated pest management. ATP-binding cassette transporters (ABC transporters) influence insect physiological performance, but their role in regulating aphid feeding behavior relevant to crop damage and virus transmission remains unknown. This study evaluated whether ABC transporter activity alters feeding phases of M. sacchari on sorghum. RESULTS: Aphids exposed to ABC transporter modulators via artificial diet and monitored using Electrical Penetration Graph (EPG) recordings showed significant reductions in salivation in E1 phase, compared with controls (P < 0.05) and an increased duration in xylem phase when treated with elacridar, an ABC transporter inhibitor. Aphids treated with dexamethasone, an ABC transporter activator, exhibited increased time spent in pathway phase compared to the controls. ATPase assays also showed significant variations in modulator-treated samples compared to the controls. CONCLUSION: These results demonstrate that transporter modulators alter feeding behaviors which might lead to reduced crop damage/virus transmission, including pathway activities, salivation, and xylem ingestion. This study opens the path to identify ABC transporters as regulators of feeding phases, and to advance the understanding of aphid-plant interactions. This new knowledge will support the development of feeding-based pest management strategies to reduce crop damage and virus transmission.

physiology↗

bioRxiv2026

Evolutionary divergence V-ATPase function in macropinocytic cup remodeling

Macropinocytosis is an evolutionarily conserved process from unicellular eukaryotes to mammals. This process relies on actin-rich protrusions beneath the plasma membrane to form a macropinocytic cup. Traditionally, V ATPase has been best studied for its role in late endosomal acidification. However, the specific roles of V-ATPase interaction with cytoskeletal machinery and its crosstalk with lipids in the formation of macropinocytic cups have not been investigated. Here, we uncover an unprecedented role of V-ATPase in shaping the macropinocytic cup in the pathogenic amoeba Entamoeba histolytica. Our results showed that the Entamoeba V-ATPase complex is associated with F-actin at macropinocytic cups. Moreover, we found that the V-ATPase complex is dynamically recruited to the macropinocytic cup and dissociates from the macropinosome. We further demonstrated that the V-ATPase V1B subunit directly binds to actin and uniquely promotes actin polymerization. The pH biosensor phosphatidic acid, revealed abundant V-ATPase complex and cytoskeleton associated proteins in its interactome. Surprisingly, the V1B subunit showed reproducible binding to phosphatidic acid and this interaction modulates actin polymerization. Collectively, our work highlights the novel role of V-ATPase in directly driving actin polymerization, in conjunction with phosphatidic acid, to shape the macropinocytic cup.

cell biology↗

bioRxiv2026

A conserved peptidase governs glucose homeostasis in Bacteroides

Glucose homeostasis is governed by peptidases across the kingdom of life. Host overconsumption of glucose transforms gut microbial compositions and activities. Here, we identify an IDE-like M16 peptidase in human gut commensal Bacteroides that controls glucose-dependent inhibition of the transcriptional regulator, Cur, which is important for intestinal colonization and host-microbial interactions. This regulatory paradigm is independent of fructose, establishing a specific pathway whereby glucose signaling hinders commensal fitness in the host. We determined that this peptidase cleaves targets of other M16-family peptidases, including insulin, to control carbon metabolism through the oxidative pentose phosphate pathway (OPPP). Furthermore, we show that peptidase activity governs the abundance of glycolytic enzymes to alter Cur activity. These findings establish that the activity of an M16 peptidase mediates changes to global transcription in Bacteroides species when glucose is abundant in the host diet.

microbiology↗

bioRxiv2026

A Statistical Method to Estimate the Population-Level Frequencies of Plasmodium falciparum Haplotypes with Pfhrp2/3 Deletions in the Presence of Mixed-Clone Infections

BackgroundThe World Health Organization (WHO) has raised concerns over increasing Pfhrp2/3 deletions, undermining the sensitivity of Pfhrp2-based rapid diagnostic tests (RDTs). Close monitoring of the population and a change in diagnostic methods are recommended if the prevalence of parasites with Pfhrp2/3 deletions exceeds 5%. In high transmission settings, accurate estimates are hampered by the frequent occurrence of mixed-clone infections (multiplicity of infection; MOI). Objective and MethodsIf parasites with and without deletions are present in an infection, standard molecular assays cannot detect the presence of the former. To accurately estimate frequencies of haplotypes with Pfhrp2/3 deletions in the presence of mixed infections, a novel statistical model that combines genetic/molecular information from Pfhrp2/3 with that from neutral markers is introduced. Maximum-likelihood estimates (MLEs) are obtained for haplotype frequencies characterized by markers at Phrp2/3 loci and loci for neutral markers. The expectation-maximization algorithm is used to derive the MLEs. The adequacy of the method (precision and accuracy) is assessed by numerical simulations. ResultsThe method was applied to an active surveillance study conducted in a tribal community in Jagdalpur, India, which enrolled febrile community members (n = 432) between October and November 2021. Four markers each at Pfhrp2 and Pfhrp3 are combined with one marker each at Pfmsp1 (which encodes P. falciparum merozoite surface protein 1) and Pfmsp2. Data from a total of 117 patients who had both P. falciparum infections and genetic information for the molecular markers underwent further analysis with the novel statistical method. ConclusionResults indicate that this novel method has promising statistical properties (asymptotic and in finite samples) and can be readily applied to real-world situations. A stable implementation of the method in R is provided. This novel approach enables accurate estimation of Pfhrp2/3 deletion frequencies in complex P. falciparum infections, addressing a key limitation of current molecular surveillance methods. Author summaryPlasmodium falciparum (Pf) causes the most severe form of human malaria, accounting for over 90% of cases. Rapid diagnostic tests (RDTs) have become a cornerstone of malaria control. These RDTs detect Pf-specific antigens in a blood drop. HRP2/3 emerged as the best antigen for such tests because it is Pf-specific and expressed in abundance. However, some parasites lack the genes that code for HRP2/3 proteins. If parasites in an infection have such gene deletions, RDT results can be false negative. The WHO considers the containment of such deletions a public health priority and recommends monitoring their prevalence. The detection of HRP deletions is challenging if parasites with and without deletions co-occur in infections because standard molecular assays cannot detect deletions in this situation. To overcome this challenge, we introduce a novel statistical method to estimate the frequency distribution of parasite variants with deletions. The method combines information from neutral molecular markers and from HRP-related markers to correct for unobservable information. Here we provide a derivation of the statistical model, a stable implementation, and test its statistical properties with synthetic and real data, thereby showing that our method is well-suited for the underlying problem.

genetics↗

bioRxiv2025

Efficient elimination of microbial infections in wounds using plasma activated water hydrogel

Surgical site infections are among the most common postoperative complications and remain a major global health concern, further intensified by increasing antimicrobial resistance. Plasma-activated water (PAW) has emerged as a novel antimicrobial strategy, though earlier studies suggested its activity depends on an acidic pH. To overcome this limitation, we previously developed a high-strength, neutral pH-buffered formulation (hs-PAbW) optimized for human clinical use, which preserved strong antimicrobial properties. In the present work, we created a hydrogel incorporating hs-PAbW at a bactericidal yet non-cytotoxic concentration (hs-PAbW-20) and evaluated its therapeutic performance in mouse wound models. In Balb/c mice, hs-PAbW-20 gel markedly reduced Pseudomonas aeruginosa and Staphylococcus aureus loads, demonstrating efficacy comparable to neomycin and soframycin. The gel also enhanced wound closure by regulating key genes involved in tissue repair. In a diabetic C57BL/6 model, hs-PAbW-20 gel similarly lowered P. aeruginosa burden and accelerated healing. Collectively, these results highlight hs-PAbW-20 gel as a promising next-generation wound therapy capable of addressing the shortcomings of traditional antibiotic-based treatments.

microbiology↗

bioRxiv2025

A high-throughput microbial glycomics platform for prebiotic development

The mammalian intestine contains diverse carbohydrate pools that govern the gut microbiome composition. Structurally distinct polysaccharides, also called glycans, are differentially consumed by gut microbial subsets and direct their abundance by controlling gene expression and metabolite production. Therefore, identifying gut microbial accessible carbohydrates (MACs) is necessary to develop new prebiotics that beneficially manipulate the gut microbiome. However, no methods exist to efficiently examine MACs in biologically-derived mixtures. Here, we present a high-throughput platform to detect MACs from various plant, animal, and microbial sources using a genome-wide library of engineered Bacteroides thetaiotaomicron (Bt) strains that harness their endogenous glycan detection machinery. We demonstrate that this platform exhibits specific and sensitive responses to glycan mixtures and use bacterially-encoded proteins to characterize a previously unknown MAC from yeast. Expanding this technology across gut Bacteroides species will generate a broadly applicable approach to characterize heterogeneous glycan mixtures and identify prebiotic substrates.

molecular biology↗

bioRxiv2025

Osmotic conditions shape fitness gains and resistance mechanisms during E. coli and T4 phage co-evolution

Environmental conditions strongly influence interactions between bacteria and bacterio-phages (phages). Here, we examined how osmolality (solute concentration) shapes the in vitro co-evolution of T4 phage and its host Escherichia coli during serial passage. When evolved independently, we observed substantial fitness gains in both bacteria and phages, particularly in high osmotic conditions. During co-evolution, however, fitness gains were limited, bacterial populations consistently evolved phage resistance, and several phage populations went extinct. Furthermore, the resistance mechanisms varied by osmolality. In lower osmolalities, mutations disrupted phage binding sites, conferring strong resistance. In higher osmolalities, mutations led to increased colonic acid production, producing a mucoid phenotype with weaker resistance. Because mucoidy has been associated with increased bacterial virulence, these findings suggest that gut-relevant osmotic conditions may constrain evolutionary trajectories, favoring resistance strategies that are less effective against phage but potentially more virulent, with important implications for phage therapy design. SignificancePhages offer a promising alternative to antibiotics, but their safety and efficacy strongly depends on the environmental conditions where the bacteria and phages interact. In the human gut, for instance, solute concentrations can vary widely due to factors like food intolerances or laxative use. In this study, we show that such variations significantly impact how bacteria and phages co-evolve. In particular, we find that in higher osmolalities, bacteria evolve phage resistance through mucoidy - a phenotype linked with increased bacterial virulence - rather than receptor loss. This highlights the need to consider environmental factors when developing phage therapies.

microbiology↗

bioRxiv2024

Frizzled1 and Frizzled2 are not redundant for competitive survival under low-Wingless levels in the developing Drosophila wing epithelium

In the Drosophila wing epithelium, canonical Wnt signaling is activated by the gradient of secreted Wingless protein (Wnt1 homolog), which interacts redundantly with the Frizzled1 and Frizzled2 receptors. While sharing overlapping functions, these receptors also have distinct non-canonical roles and exhibit differential expression patterns along the Wingless gradient. Moreover, Frizzled2, unlike Frizzled1, is thought to be essential for sustaining low-level Wingless signaling and promoting cell survival in the absence of the ligand. This raises the possibility of the two receptors acting differently along the Wingless gradient. In this study, we investigated the role of these receptors in cell survival across varying Wingless levels. We find that the loss of Frizzled2 in cells at a distance from the Wingless-producing cells--where Wingless levels are low-- leads to competitive elimination of cells. In contrast, Frizzled1 is dispensable for cell survival, regardless of distance from the Wingless source. Our findings show that Frizzled2 is essential for competitive cell survival under low-Wingless conditions and the two receptors are not equally redundant across the Wingless concentration gradient, providing insight into a mechanism for spatial and temporal precision in developmental signaling.

developmental biology↗

bioRxiv2024

Glutamic acid-lysine (EK) rich motif of RabD2 self-associates and regulates pathogenesis through multivesicular bodies pathway in E. histolytica

Entamoeba histolytica, an enteric pathogen, causes disease by adhering to and destroying the host tissues. The interactions between the parasite and host tissue enable rewiring of the gene expression and global membrane trafficking in the parasite. A fine balance between cargoes/receptors endocytosis and exocytosis is required to establish infection in the host. Multivesicular bodies (MVBs) act as sorting platforms, delivering cargoes/receptors to lysosomes for degradation or secreting their content through plasma membrane fusion. Some of the small GTPases are known to control MVB biogenesis in various organisms. However, the functional contribution of Rab GTPases in MVB biogenesis is poorly studied in E. histolytica. Here, we identified a novel atypical protein RabD2, with an N-terminal glutamic acid-lysine rich motif and a C-terminal conserved Rab domain. Our biochemical and cell biological assays provide evidence that RabD2 self-associates, and this interaction is controlled by the N-terminal EK-rich motif and the GTPase activity mutants (in a nucleotide-specific manner). RabD2 localizes on the surface of MVBs and controls their biogenesis. In line with these findings, overexpression of RabD2 upregulates global ubiquitination, directing the down regulation of the heavy chain of GalNAc lectin, ultimately leading to decreased adherence of E. histolytica trophozoites to host cells. Thus, amoebic RabD2 is a new class of Rab protein that forms high-ordered self-association variants and regulates the pathogenicity of E. histolytica through the biogenesis of MVBs. Author SummaryAmoebiasis is an enteral infection caused by Entamoeba histolytica that primarily remains asymptomatic but can eventually result in systemic complications like amoebic dysentery, liver abscess, and pulmonary effusions. Recent studies showed that Entamoeba ubiquitin is a robust antigen and linked with the invasive amoebiasis patient samples. Here, we identified a novel RabD2 that self-associates via its glutamic acid-lysine rich motif that causes high ubiquitination levels and biogenesis of multivesicular bodies. We uncovered for the first time that RabD2-mediated ubiquitin-dependent pathway is involved in the down regulation of the notable antigenic marker heavy chain of galactose-N-acetylgalactosamine lectin and thereby controls the parasite adherence to host cells. Further studies on crosstalk between parasite ubiquitination and antigenic receptors downregulation provide insights into how parasites use these strategies to establish the infection in the host intestine.

microbiology↗

bioRxiv2024

Hierarchical glycolytic pathways control the carbohydrate utilization regulator in human gut Bacteroides

Human dietary choices control the gut microbiome. Industrialized populations consume abundant amounts of glucose and fructose, resulting in microbe-dependent intestinal disorders. Simple sugars inhibit the carbohydrate utilization regulator (Cur), a transcription factor in members of the prominent gut bacterial phylum, Bacteroidetes. Cur controls products necessary for carbohydrate utilization, host immunomodulation, and intestinal colonization. Here, we demonstrate how simple sugars decrease Cur activity in the mammalian gut. Our findings in two Bacteroides species show that ATP-dependent fructose-1,6-bisphosphate (FBP) synthesis is necessary for glucose or fructose to inhibit Cur, but dispensable for growth because of an essential pyrophosphate (PPi)-dependent enzyme. Furthermore, we show that ATP-dependent FBP synthesis is required to regulate Cur in the gut but does not contribute to fitness when cur is absent, indicating PPi is sufficient to drive glycolysis in these bacteria. Our findings reveal how sugar-rich diets inhibit Cur, thereby disrupting Bacteroides fitness and diminishing products that are beneficial to the host.

microbiology↗

bioRxiv2024

Drought resistance and improved yield result from modified malate metabolism in guard and vascular companion cells

Drought is a major threat to food security. Water loss through stomata is an inevitable consequence of CO2 uptake, and water deficit inhibits plant growth, making it challenging to develop drought-resistant strategies without compromising yield. Here, we generated tobacco plants expressing a maize NADP-dependent malate decarboxylating enzyme in stomata and vascular cells (ME plants), which show higher seed yield and faster maturation compared to wild-type (WT) plants under normal irrigation and after drought. While WT plants die after 45 days of drought, ME plants survive without any adverse effects on seed production. In addition, ME plants exhibit improved photosynthetic efficiency despite reduced stomatal conductance and changes in stem morphology, which are likely related to their ability to withstand drought. We propose that enhanced C4-like biochemistry in cells surrounding the vascular system and increased sugar export likely compensated for the reduced stomatal conductance in ME plants. The study demonstrates that cell-targeted metabolic modifications can avoid pleiotropic effects and facilitate the stacking of beneficial traits to improve crop design. Significance StatementDrought is one of the biggest threats to global food security, and its impact on crop yield is expected to worsen due to climate change. Traditionally, drought resistance has often come at the expense of yield, creating a negative trade-off. However, we present here a promising solution to this challenge. We have developed a novel approach that successfully uncouples the negative balance between drought resistance and yield. By introducing a maize enzyme into specific tobacco cells, we have created drought-resistant plants with faster growth and higher seed yield. Most importantly, after prolonged drought, while the wild type dies, the modified plants maintain their high yield. This technology paves the way for greater food security and resilience to climate change.

plant biology↗

bioRxiv2022

A novel maxillofacial technique to deliver drugs to the visual pathway, the optic nerve and the retina using the glymphatic system.

The blood neural barriers are formidable barriers that prevent delivery of drugs into the eye and the brain. Currently, large biologics are used for treating many diseases of the eye and the brain. But the blood retinal barrier and the blood brain barrier prevent entry of these useful drugs into the eye and the brain respectively. Hence, there is a need for a drug delivery technique to bypass these natural barriers. Bevacizumab (Avastin) is a full length humanized monoclonal antibody with a molecular weight of 149kda. It binds to circulating vascular endothelial growth factor A and prevents interaction with vascular endothelial growth receptors. This results in blocking endothelial response and tumor vascularization. Bevacizumab is used to prevent choroidal neovascularization in age related macular degeneration and to prevent retinal neovascularization in diabetic retinopathy. It is also used for treating certain types of brain cancer. But it crosses neither the blood retinal barrier nor the blood brain barrier. This in vivo mouse study assessed the delivery of a commercial formulation of bevacizumab into the retina of mice using different ocular techniques like topical drops, subconjunctival injection, intravitreal injection and a novel maxillofacial technique. The objective was to assess whether the novel maxillofacial drug delivery technique could deliver drugs into the retina and to compare the efficacy of the maxillofacial technique with the mentioned ocular techniques. The distribution of bevacizumab was further compared with retinoschisin which is a small protein with a molecular weight of 24kda. Intravitreal injection and maxillofacial technique were effective in delivering drugs into the retina. In addition, the maxillofacial technique could target the brain including regions involved in the visual pathway and the optic nerve. The glymphatic pathway could also be targeted for drug delivery. Drug was also detected in the contralateral optic nerve and retina. Based on our study findings, we propose a new concept to explain the presence of the drug in the contralateral eye. We propose that after maxillofacial drug delivery, early distribution of the drug can occur in the CSF at the optic chiasma from the brain via the glymphatic system. In the case of the intravitreal injection, the drug from the experimental eye may be cleared through the glymphatic pathway of the ipsilateral optic nerve into the CSF surrounding the nerve. The crossover of the ipsilateral optic nerve fibers at the optic chiasma can result in further distribution of the drug in the CSF at the optic chiasma. From the region of the optic chiasma, the drug can distribute into the CSF surrounding the contralateral optic nerve. The drug can be then distributed into the contralateral optic nerve through the glymphatic pathway and be delivered into the contralateral eye. The drug can be further cleared into the aqueous of the contralateral eye through the anterior clearance pathway.

neuroscience↗

bioRxiv2022

Live visualization of cytosolic and endoplasmic reticulum redox potential in zebrafish embryos reveals region-specific differences

Redox homeostasis is an integral part of many cellular processes, and its perturbation is associated with conditions such as diabetes, aging, and neurodegenerative disorders. Redox homeostasis or redox potential in organelles is maintained within a particular range to facilitate the organelle specific cellular redox reactions. Previous studies using yeast, cell systems, and nematodes have demonstrated that the Endoplasmic Reticulum (ER) has a more oxidizing environment while the cytosol exhibits a reducing redox potential. However, we know very little about how universal this phenomenon is. We created transgenic zebrafish (Danio rerio) lines with roGFP sensors targeted to the ER and cytosol for studying physiological redox potential at the systems level. In the process, we also characterized the ER-targeting signal sequence in D. rerio for the first time. Measurements of the redox state in live embryos found that the endoplasmic reticulum exhibits deviations from its expected oxidizing redox state in different regions of the developing embryos. The ER is far more reducing than expected in certain tissues of the embryo. Cytosol also exhibited unexpected redox states in some parts of the embryo. Notably, the brain showed regions with unexpected redox states in both the ER and the cytosol. Tissue-specific differences in ER-redox potential became even more evident in a transgenic line expressing the more sensitive roGFPiE variant. Thus, live monitoring of redox potential across the developing zebrafish embryos revealed unanticipated redox states of the ER that will require new biological definitions.

biochemistry↗

bioRxiv2020

Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection

The immune response to SARS-CoV-2 is critical in both controlling primary infection and preventing re-infection. However, there is concern that immune responses following natural infection may not be sustained and that this may predispose to recurrent infection. We analysed the magnitude and phenotype of the SARS-CoV-2 cellular immune response in 100 donors at six months following primary infection and related this to the profile of antibody level against spike, nucleoprotein and RBD over the previous six months. T-cell immune responses to SARS-CoV-2 were present by ELISPOT and/or ICS analysis in all donors and are characterised by predominant CD4+ T cell responses with strong IL-2 cytokine expression. Median T-cell responses were 50% higher in donors who had experienced an initial symptomatic infection indicating that the severity of primary infection establishes a setpoint for cellular immunity that lasts for at least 6 months. The T-cell responses to both spike and nucleoprotein/membrane proteins were strongly correlated with the peak antibody level against each protein. The rate of decline in antibody level varied between individuals and higher levels of nucleoprotein-specific T cells were associated with preservation of NP-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T-cell responses are retained at six months following infection although the magnitude of this response is related to the clinical features of primary infection.

immunology↗

bioRxiv2020

GroEL/ES Buffers Entropic Traps In Folding Pathway During Evolution Of A Model Substrate

The folding landscape of proteins can change during evolution with the accumulation of mutations that may introduce entropic or enthalpic barriers in the protein folding pathway, making it a possible substrate of molecular chaperones in vivo. Can the nature of such physical barriers of folding dictate the feasibility of chaperone-assistance? To address this, we have simulated the evolutionary step to chaperone-dependence keeping GroEL/ES as the target chaperone and GFP as a model protein in an unbiased screen. We find that the mutation conferring GroEL/ES dependence in vivo and in vitro encode an entropic trap in the folding pathway rescued by the chaperonin. Additionally, GroEL/ES can edit the formation of non-native contacts similar to DnaK/J/E machinery. However, this capability is not utilized by the substrates in vivo. As a consequence, GroEL/ES caters to buffer mutations that predominantly cause entropic traps, despite possessing the capacity to edit both enthalpic and entropic traps in the folding pathway of the substrate protein.

molecular biology↗

bioRxiv2020

Mechanism of action of HBV capsid assembly modulators predicted from binding to early assembly intermediates

Interfering with the self-assembly of virus nucleocapsids is a promising approach for the development of novel antiviral agents. Applied to hepatitis B virus (HBV), this approach has led to several classes of capsid assembly modulators (CAMs) that target the virus by either accelerating nucleocapsid assembly or misdirecting it into non-capsid-like particles. Here, we have assessed the structures of early nucleocapsid assembly intermediates, with and without bound CAMs, using molecular dynamics simulations. We find that distinct conformations of the intermediates are induced depending on whether the bound CAM accelerates or misdirects assembly; these structures are predictive of the final assembly. We also selected non-capsid-like structures from our simulations for virtual screening, resulting in the discovery of several compounds with moderate anti-viral activity and low toxicity. Cryo-electron microscopy and capsid melting experiments suggest that our compounds possess a novel mechanism for assembly modulation, potentially opening new avenues for HBV inhibition.

molecular biology↗

bioRxiv2019

Distinct metabolic states of a cell guide alternate fates of mutational buffering through altered proteostasis

Changes in metabolism can alter the cellular milieu; can this also change intracellular proteostasis? Since proteostasis can modulate mutational buffering, if change in metabolism has the ability to change proteostasis, arguably, it should also alter mutational buffering. Building on this, we find that altered cellular metabolic states in E. coli buffer distinct mutations. Buffered-mutants had folding problems in vivo and were differently chaperoned in different metabolic states. Notably, this assistance was dependent upon the metabolites and not on the increase in canonical chaperone machineries. Additionally, we were able to reconstitute the folding assistance afforded by metabolites in vitro and propose that changes in metabolite concentrations have the potential to alter proteostasis. Collectively, we unravel that the metabolite pools are bona fide members of proteostasis and aid in mutational buffering. Given the plasticity in cellular metabolism, we posit that metabolic alterations may play an important role in the positive or negative regulation of proteostasis.

biochemistry↗