Biology subjects

Sheykhkarimli, D.

Publications and source records attributed to Sheykhkarimli, D..

5 recordsLinked to original sources

bioRxiv2026

A genetic screen to identify novel interactions of the phosphatidylinositol phosphate signaling pathway in Drosophila spermatogenesis

Phosphatidylinositol (PI) phosphates (PIPs) are membrane lipids with crucial roles in intracellular signaling, membrane trafficking and cytoskeletal organization. To perturb PIP function in Drosophila melanogaster sperm development, we previously expressed the Salmonella PIP phosphatase SigD (also known as SopB) under control of a spermatocyte- specific promoter. SigD expression results in reduced levels of plasma membrane PI 4,5-bisphosphate [PI(4,5)P2; henceforth PIP2] and male sterility. Transgenic lines expressing high levels of SigD (SigD-high) exhibit defects in spermatocyte cytokinesis, ciliary transition zone maturation and spermatid elongation, whereas lines expressing low levels of SigD (SigD-low) have defects in nuclear shaping and spermatid cell polarization. To further investigate the role of PIPs during Drosophila sperm development, we conducted a sensitized genetic screen to identify suppressors and enhancers of SigD-low phenotypes. From a screen of 760 chromosomal deficiencies spanning 83.6% of chromosomes 2 and 3, we identified 80 interacting regions that were further narrowed down to 40 individual suppressors. Among the strongest interactors were genes involved in microtubule dynamics, nucleocytoplasmic transport and membrane trafficking. The novel genetic interactions identified by our screen pave the way for further investigation into molecular mechanisms underlying the affected aspects of sperm development.

genetics↗

bioRxiv2024

A comprehensive two-hybrid analysis to explore the L. pneumophila effector-effector interactome

Legionella pneumophila uses over 300 translocated effector proteins to rewire host cells during infection and create a replicative niche for intracellular growth. To date, several studies have identified L. pneumophila effectors that indirectly and directly regulate the activity of other effectors, providing an additional layer of regulatory complexity. Amongst these are "metaeffectors" - a special class of effectors that regulate the activity of other effectors once inside the host. A defining feature of metaeffectors is direct, physical interaction with a target effector. Metaeffector identification to date has depended on phenotypes in heterologous systems and experimental serendipity. Using a multiplexed, recombinant-barcode-based yeast two-hybrid technology we screened for protein-protein interactions amongst all L. pneumophila effectors and several components of the Dot/Icm type IV secretion system (>167,000 protein combinations). Of the 52 protein interactions identified by this approach, 44 are novel protein interactions, including ten novel effector-effector interactions (doubling the number of known effector-effector interactions).

microbiology↗

bioRxiv2024

Quantitative genetics of natural S. cerevisiae strains upon sexual mating reveals heritable determinants of cellular fitness

Quantitative genetics requires large datasets of diverse phenotyped-genotyped strains from the same species. A special need is for such archived biological material and computerized data in sexually reproducing individuals from a species. Here we leverage sexual mating among close to 100 diverse natural isolates of the yeast S. cerevisiae that form about 4,000 hybrids combinations in several ecologically relevant growth conditions. In a first genetic study of this new resource we focus on fitness measurements and its modes of inheritance as a quantitative trait from parents to offspring hybrids. We employ genomic barcoding of all strains and a barcode recombination technique to follow hybrids of each successful mate combination. For all parents, and separately for all offspring hybrids we measure fitness under each condition. We focus on the inheritance of fitness, the ultimate evolutionary trait, and its inheritance as a quantitative trait upon sexual mating. Predicting hybrid fitness given parental parameters is a major challenge as it is likely multi-factorial. We find that hybrids fitness in fermentable carbon source correlates positively, yet modestly, with parental fitness, while on non-fermentable carbon, hybrid fitness shows no detectable correlation with parental fitness. Instead, the non-fermentable condition, hybrid fitness increases sharply with genetic distance between their parents, suggesting that outbreeding maximizes fitness irrespective of parental fitness at that condition. The number of minor alleles in the genome of each hybrid, analogous to polygenic risk score in classical genetics, negatively correlates with fitness in both conditions. Fitness inheritance can be explained by either a dominance or a co-dominance modes of inheritance, in the non-fermentable and fermentable conditions respectively. Our newly suggested biological resource and data provide new foundations for a quantitative research in genetics and evolution upon sexual mating. Furthermore, our barcoded strains and mating tracking method provide an important research resource for the yeast community.

genetics↗

bioRxiv2021

A map of direct SARS-CoV-2 protein interactions implicates specific human host processes

Key steps in viral propagation, immune suppression, and pathology are mediated by direct, binary, physical interactions between viral and host proteins. To understand the biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we generated an unbiased systematic map of binary interactions between viral and host proteins, complementing previous co-complex association maps by conveying more direct mechanistic understanding and potentially enabling targeted disruption of direct interactions. To this end, we deployed two parallel strategies, identifying 205 virus-host and 27 intraviral binary interactions amongst 171 host and 19 viral proteins, and confirming high quality of these interactions via a calibrated orthogonal assay. Host proteins interacting with SARS-CoV-2 proteins are enriched in various cellular processes, including immune signaling and inflammation, protein ubiquitination, and membrane trafficking. Specific subnetworks provide new hypotheses related to viral modulation of host protein homeostasis and T-cell regulation. The binary virus-host protein interactions we identified can now be prioritized as targets for therapeutic intervention. More generally, we provide a resource of systematic maps describing which SARS-CoV-2 and human proteins interact directly.

systems biology↗

bioRxiv2020

Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

The worldwide SARS-CoV-2 outbreak poses a serious challenge to human societies and economies. SARS-CoV-2 proteins orchestrate complex pathogenic mechanisms that underlie COVID-19 disease. Thus, understanding how viral polypeptides rewire host protein networks enables better-founded therapeutic research. In complement to existing proteomic studies, in this study we define the first proximal interaction network of SARS-CoV-2 proteins, at the whole proteome level in human cells. Applying a proximity-dependent biotinylation (BioID)-based approach greatly expanded the current knowledge by detecting interactions within poorly soluble compartments, transient, and/or of weak affinity in living cells. Our BioID study was complemented by a stringent filtering and uncovered 2,128 unique cellular targets (1,717 not previously associated with SARS-CoV-1 or 2 proteins) connected to the N- and C-ter BioID-tagged 28 SARS-CoV-2 proteins by a total of 5,415 (5,236 new) proximal interactions. In order to facilitate data exploitation, an innovative interactive 3D web interface was developed to allow customized analysis and exploration of the landscape of interactions (accessible at http://www.sars-cov-2-interactome.org/). Interestingly, 342 membrane proteins including interferon and interleukin pathways factors, were associated with specific viral proteins. We uncovered ORF7a and ORF7b protein proximal partners that could be related to anosmia and ageusia symptoms. Moreover, comparing proximal interactomes in basal and infection-mimicking conditions (poly(I:C) treatment) allowed us to detect novel links with major antiviral response pathway components, such as ORF9b with MAVS and ISG20; N with PKR and TARB2; NSP2 with RIG-I and STAT1; NSP16 with PARP9-DTX3L. Altogether, our study provides an unprecedented comprehensive resource for understanding how SARS-CoV-2 proteins orchestrate host proteome remodeling and innate immune response evasion, which can inform development of targeted therapeutic strategies.

systems biology↗