Biology subjects

Syed, Z. A.

Publications and source records attributed to Syed, Z. A..

7 recordsLinked to original sources

bioRxiv2026

BLOC1S1 regulates autolysosomal and exosomal dynamics during CD4⁺ T cell differentiation

Although the endolysosome system is central to intracellular recycling, signal transduction, and intercellular communication via exocytosis, its role in immunoregulation remains incompletely defined. We recently identified that CD4+ T cell-specific depletion of BLOC1S1, a component of multiprotein complexes regulating endolysosomal biology, predisposes toward type 2 (Th2) immunity. We therefore hypothesized that the study of BLOC1S1-deficient CD4+ T cells would expand our understanding of endolysosomal dynamics in Th2 function. Here, we demonstrate that CD4+ T cell BLOC1S1 deficiency resulted in aberrant lysosomal distribution, accumulation of endosomal vesicles, and increased exocytosis, which collectively correlated with enhanced Th2 immune responses. The phenotype was associated with upregulation of key components of the exocytosis machinery, including RAB11 and VAMP7. Functional inhibition of these vesicle trafficking proteins following siRNA knockdown of RAB11 and VAMP7 significantly attenuated Th2 cytokine secretion in BLOC1S1-deficient CD4+ T cells, highlighting their essential role in exosome-mediated cytokine export. Furthermore, exosomes derived from BLOC1S1-deficient CD4+ T cells promoted Th2 polarization in recipient cells, indicating a mechanism of intracellular amplification. Together, these findings identify BLOC1S1 as a critical regulator of lysosomal dynamics and exocytic vesicle fusion, thereby linking intracellular trafficking mechanisms to Th2 immune regulation.

immunology↗

bioRxiv2025

The aging transcriptome: a condition-dependent response to a deteriorating soma

Organismal function requires precise gene expression, as deviations reduce fitness and can cause disease. The widespread expression changes characteristic of old age therefore suggests that aging itself may partly stem from gene dysregulation. Alternatively, many of these changes may represent a plastic response to somatic decline, tuning the organism to an altered physiological state. We tested the latter hypothesis by experimentally reducing the condition of Drosophila melanogaster females independently of age and comparing the resulting expression changes with those occurring naturally during aging. Consistent with the plasticity hypothesis, we find substantial overlap between genes responding to reduced condition and old age. Downregulated genes are enriched for metabolic functions, with a consistent, albeit weaker, association with mitochondrial function and cytoplasmic translation, while upregulated genes relate to genome maintenance. Both old age and reduced condition also cause downregulation of tissue-specific and female-biased genes, as expected when energy is reallocated to core cellular processes. In line with a coordinated transcriptional response to old age, both down- and upregulated genes within enriched functional categories show reduced expression variability and experience strong purifying selection. Collectively, our results support that the aging soma elicits a plastic transcriptional program that adjusts the organism to a declining physiological condition, implying that many age-related expression changes mitigate rather than accelerate somatic aging. These findings call for a more nuanced view of the causes and consequences of age-related transcriptional change, with implications for both theoretical and applied research on aging and disease.

genetics↗

bioRxiv2025

A single catalytic domain residue regulates the substrate specificity of a mucin-type O-glycosyltransferase in salivary gland function

Human GalNAc-T1 is a ubiquitously expressed mucin-type O-glycosyltransferase that modulates various biological pathways, including immunity, extracellular matrix formation, and salivary gland development and function. However, substrates of GalNAc-T1 are mostly unknown and the mechanistic details of regulation are not well characterized. Here, we investigate the role of the Drosophila melanogaster GalNAc-T1 ortholog PGANT5 in salivary glands and provide structural and biochemical details into its mechanism of O-glycosylation. We find that loss of pgant5 causes irregular secretory granule morphology, altered mucin packaging, and disruption of secretion. Alternative splicing of pgant5 yields two isoforms, pgant5A and pgant5B, with higher expression of pgant5A in salivary glands. Rescue with pgant5A, but not pgant5B, partially restores secretory granule morphology and salivary gland function. A single residue difference within the substrate binding pockets of PGANT5A and PGANT5B increases the in vitro activity and specificity of PGANT5A towards salivary gland mucins relative to PGANT5B, corroborating the in vivo expression and role of pgant5A in salivary glands. Our data additionally provide new insights into a catalytic domain motif that regulates GalNAc-T activity. Overall, our studies illustrate how alternative splicing of an O-glycosyltransferase that results in modest amino acid changes can influence substrate specificity to regulate tissue-specific biological functions.

biochemistry↗

bioRxiv2023

Single-fly assemblies fill major phylogenomic gaps across the Drosophilidae Tree of Life

Long-read sequencing is driving rapid progress in genome assembly across all major groups of life, including species of the family Drosophilidae, a longtime model system for genetics, genomics, and evolution. We previously developed a cost-effective hybrid Oxford Nanopore (ONT) long-read and Illumina short-read sequencing approach and used it to assemble 101 drosophilid genomes from laboratory cultures, greatly increasing the number of genome assemblies for this taxonomic group. The next major challenge is to address the laboratory culture bias in taxon sampling by sequencing genomes of species that cannot easily be reared in the lab. Here, we build upon our previous methods to perform amplification-free ONT sequencing of single wild flies obtained either directly from the field or from ethanol-preserved specimens in museum collections, greatly improving the representation of lesser studied drosophilid taxa in whole-genome data. Using Illumina Novaseq X Plus and ONT P2 sequencers with R10.4.1 chemistry, we set a new benchmark for inexpensive hybrid genome assembly at US $150 per genome while assembling genomes from as little as 35 ng of genomic DNA from a single fly. We present 183 new genome assemblies for 179 species as a resource for drosophilid systematics, phylogenetics, and comparative genomics. Of these genomes, 62 are from pooled lab strains and 121 from single adult flies. Despite the sample limitations of working with small insects, most single-fly diploid assemblies are comparable in contiguity (>1Mb contig N50), completeness (>98% complete dipteran BUSCOs), and accuracy (>QV40 genome-wide with ONT R10.4.1) to assemblies from inbred lines. We present a well-resolved multi-locus phylogeny for 360 drosophilid and 4 outgroup species encompassing all publicly available (as of August 2023) genomes for this group. Finally, we present a Progressive Cactus whole-genome, reference-free alignment built from a subset of 298 suitably high-quality drosophilid genomes. The new assemblies and alignment, along with updated laboratory protocols and computational pipelines, are released as an open resource and as a tool for studying evolution at the scale of an entire insect family.

evolutionary biology↗

bioRxiv2021

Orchestrated Restructuring Events During Secretory Granule Maturation Mediate Intragranular Cargo Segregation

Regulated secretion is an essential process where proteins are packaged into membranous secretory vesicles. However, the details of cargo packaging and secretory granule maturation are largely unknown. Here, we demonstrate that multiple distinct proteins undergo intragranular restructuring during secretory granule maturation in vivo, resulting in spatial segregation of distinct protein components within the same granule. Furthermore, through a combination of genetics and multimodality imaging, we demonstrate the molecular identity of each distinct intragranular structure. We further identify temporally-regulated genes that are essential for the restructuring events, including those controlling pH (Vha16-1), Cl- ions (Clic and ClC-c) and Ca2+ ions (fwe). Finally, we show that altered cargo glycosylation influences dimensions of these structures, thereby affecting secretory granule morphology. This study elucidates key steps and factors involved in intragranular, rather than intergranular segregation of cargo through regulated restructuring events during secretory granule maturation. Understanding how multiple distinct proteins are efficiently packaged into and secreted from the same secretory granule may provide insight into diseases resulting from defects in secretion.

cell biology↗

bioRxiv2020

Evolutionary genetics of Drosophila melanogaster immunity: role of the X chromosome and sex-specific dominance

Intralocus Sexual Conflict (IaSC) ensues when males and females of the same species experience divergent selection on shared traits. A large number of traits have been implicated in IaSC and there is growing evidence for sexual antagonism associated with immunity. X chromosomes are thought to be hotspots of sexually antagonistic genetic variation and have been shown to harbour substantial immunity-related genetic variation. Here, using interpopulation crosses and cytogenetic cloning, we investigated the role of the X chromosome in improved immune response of laboratory populations of the fruit-fly Drosophila melanogaster selected against systemic infection by Pseudomonas entomophila. We could not detect any contribution of the X chromosome in the evolved immune response of our selected populations. However, we found strong evidence of sex-specific dominance related to immunity in our populations. Our results indicate that alleles that confer a superior immune response to the selected populations are, on average, partially dominant in females but partially recessive in males. We argue that sex-specific dominance over immunity evolved as a by-product of sexually antagonistic selection in the wild ancestors of our populations. We also highlight sex-specific dominance as a potential mechanism of sex differences in immunity, with population-level sex differences primarily driven by sex differences in heterozygotes.

evolutionary biology↗

bioRxiv2017

Pathogen Dependent Phenotypic But No Genetic Correlation Between Sexual Activity And Immunity In Male Drosophila melanogaster Subjected To Differential Sexual Selection

The theory of trade-off suggest that limited resources should lead to trade-off in resource intensive traits such as immunity related and sexually selected traits in males. Alternatively, sexual exaggerations can also act as an honest indicator of underlying immunocompetence, leading to positive correlations between these traits. Several studies have addressed this question using experimental evolution. However, they have rarely used ecologically relevant pathogens and fitness measurement (e.g., measuring post-infection survivorship) to find correlations between sexual selection and immunity. Here we attempt to address this caveat by evolving populations of Drosophila melanogaster under differential sexual selection. After more than hundred generations, we infected virgin and mated males from each population with three pathogenic bacteria: Pseudomonas entomophila (Pe), Staphylococcus succinus (Ss) and Providentia rettgeri (Pr). Fitness was measured as either post-infection survivorship (Pe and Ss) or bacterial clearance ability (Pr). Contrary to expectations, sexual selection had no evolutionary effect on male fitness against any of the pathogens. Moreover, mating had a beneficial effect against Pe and Pr, but no effect against Ss, suggesting pathogen specific phenotypic correlations between mating and immunity. Following these results, we discuss the significance of using ecologically relevant pathogens and quantifying host fitness while studying sexual selection-immunity correlations.

evolutionary biology↗