Biology subjects

Zaidi, Z.

Publications and source records attributed to Zaidi, Z..

7 recordsLinked to original sources

bioRxiv2025

Tex15 is required for vomeronasal sensory neuron diversity and male pheromone detection

The mouse vomeronasal organ (VNO) detects pheromones, which provide vital information needed to find a mate, detect predators, or alert to the presence of an intruder. Within the VNO, pheromones are sensed by two families of G-protein Coupled Receptors (GPCRs) the type 1 and type 2 vomeronasal receptors (V1Rs and V2Rs). However, little is known about the regulatory mechanisms that control the expression of V1R and V2R genes by vomeronasal sensory neurons (VSNs). Here we identify a transcriptional repressor, Testis-expressed gene 15 (Tex15), that regulates vomeronasal receptor gene choice and is required for the proper functioning of the vomeronasal system in regulating male behavior. We find that Tex15 is transiently expressed by VSN precursors prior to strong VR gene expression. The absence of Tex15 results in a pervasive change in the expression of V1R and V2R genes, which results in a less diverse repertoire of VR expressing cells and includes a dramatic reduction in the expression of specific receptors that have been tied to intermale aggression. Accordingly, Tex15 knockout mice exhibit lowered activation in the Accessory Olfactory Bulb (AOB) after exposure to male odorants, and a loss of stereotyped aggression between male mice. Taken together, these results show that Tex15 plays a critical role in pheromone sensing by ensuring that VSNs express a diverse set of receptor proteins.

molecular biology↗

bioRxiv2025

Arg80 Orchestrates a Metabolic-Translational Proteostasis Network in S. cerevisiae

Proteostasis or protein homeostasis is essential for cellular function and organismal health. While many models of cytosolic proteostasis emphasize heat shock response as critical for regulating cellular protein folding, a comprehensive understanding of transcriptional modules that may regulate cytosolic protein folding is lacking. Through a focused screening for transcription factors, we provide evidence that a number of transcriptional programs unlinked to canonical proteotoxic response are involved in maintaining cellular homeostasis of protein folding. Among these, Arg80, a regulator of arginine metabolism, was activated during proteotoxic stress and found essential for mitigating it. We show that proteostasis imbalance in arg80{Delta} cells is caused by excess arginine accumulation, which is sufficient to impair protein folding. We reveal a complex interplay between arginine repression (Arg80), trehalose biosynthesis (Tps2), and the integrated stress response (Gcn2) in combating proteotoxic insults. We posit that multiple metabolic pathways integrate with classical protein quality control networks to regulate the protein folding environment. Harnessing these metabolic circuits may offer new avenues to modulate proteostasis when needed.

systems biology↗

bioRxiv2025

Laboratory adaptive evolution of thermotolerance is linked to the evolution of a robust proteostasis in S. cerevisiae

Thermophilic organisms have evolved a proteome that resists thermal denaturation. While the evolution of their complete proteome would require multiple generations, early on, organisms would need to develop strategies to survive at high temperatures despite their thermolabile proteome. We hypothesized that the organisms would do this by reinforcing their proteostasis capacity. We tested this hypothesis using adaptive laboratory evolution of thermotolerance in Saccharomyces cerevisiae and found that the cells reproducibly evolved better proteostasis capacity in short-term evolution experiments. However, rather than improving the global proteostasis capacity, most of the evolved strains demonstrated enhanced capacity to tackle misfolding in the Endoplasmic Reticulum (ER), specifically by increasing their capacity for ER-associated degradation (ERAD). Given the strong selective advantage of these strains, we posit that protein folding in the ER may be exquisitely sensitive to chronic thermal stress and may act as an early indicator for adaptation to higher temperatures.

evolutionary biology↗

bioRxiv2024

Fitness defects due to cytosolic protein misfolding in S. cerevisiae can be alleviated by decreasing mitochondrial protein import capacity

Protein misfolding affects cellular fitness. This can be caused due to the toxic aggregation of one species of protein or global protein misfolding events. Since the fitness defect arises due to the multi-modal effect of misfolding, there is no consensus mechanism to alleviate this fitness defect. Here, we used adaptive laboratory evolution of thermotolerance to identify pathways contributing to proteotoxic stress resistance in S. cerevisiae. Our results suggest a link between thermotolerance and proteotoxicity resistance, majorly routed through the loss of mitochondrial DNA. Loss of mitochondrial DNA decreased the association of mistargeted misfolded proteins on the mitochondrial surface and altered the cellular response to proteostasis to enhance protein quality control associated degradation. We show that a decrease in the abundance of import channels is sufficient to mimic the loss of mtDNA and increase cellular proteostasis. Thus, we uncover a cryptic interorganellar cooperation in combating proteotoxicity in yeast.

molecular biology↗

bioRxiv2023

A Bioluminescent Activity Dependent (BLADe) Platform for Converting Neuronal Activity to Photoreceptor Activation

Genetically encoded sensors and actuators have advanced the ability to observe and manipulate cellular activity, yet few non-invasive strategies enable cells to directly couple their intracellular states to user-defined outputs. We promote a bioluminescent activity-dependent (BLADe) platform that facilitates programmable feedback through genetically encoded light generation. Using calcium (Ca{superscript 2}) flux as a model, we engineered a Ca{superscript 2}-dependent luciferase that functions as an activity-gated light source capable of photoactivating light-sensing actuators. As an initial demonstration of the versatility of this platform we present two separate use cases in neurons. In the first application, the presence of luciferin triggers Ca{superscript 2} dependent local illumination that provides activity dependent gene expression by activating a light-sensitive transcription factor. In the second application, neuronal activity-driven Ca{superscript 2} fluctuations via locally generated bioluminescence control neural dynamics through opsin activation in single cells, populations and intact tissue. BLADe can be expanded to couple any signal that bioluminescent enzymes can be engineered to detect with the wide variety of photosensing actuators. This modular strategy of coupling an activity dependent light emitter to a light sensing actuator offers, in principle, a generalizable framework for state dependent cell-autonomous control across biological systems.

neuroscience↗

bioRxiv2021

A phospho-switch at Acinus-Serine437 controls autophagic responses to cadmium exposure and neurodegenerative stress

Neuronal health depends on quality control functions of autophagy, but mechanisms regulating neuronal autophagy are poorly understood. Previously, we showed that in Drosophila starvation-independent quality control autophagy is regulated by Acinus and the Cdk5-dependent phosphorylation of its serine437 (Nandi et al., 2017). Here, we identify the phosphatase that counterbalances this activity and provides for the dynamic nature of Acinus-S437 phosphorylation. A genetic screen identified six phosphatases that genetically interacted with an Acinus gain-of-function model. Among these, loss of function of only one, the PPM-type phosphatase Nil (CG6036), enhanced pS437-Acinus levels. Cdk5-dependent phosphorylation of Acinus serine437 in nil1 animals elevates neuronal autophagy and reduces the accumulation of polyQ proteins in a Drosophila Huntingtons disease model. Consistent with previous findings that Cd2+ inhibits PPM-type phosphatases, Cd2+-exposure elevated Acinus-serine437 phosphorylation which was necessary for increased neuronal autophagy and protection against Cd2+-induced cytotoxicity. Together, our data establish the Acinus- S437 phospho-switch as critical integrator of multiple stress signals regulating neuronal autophagy.

cell 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↗