Biology subjects

Rossini, S.

Publications and source records attributed to Rossini, S..

4 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↗

bioRxiv2025

Spatial proteomics reveals mechanisms of cell-intrinsic tryptophan metabolism controlling ovarian cancer survival

Indole-2,3-dioxygenase (IDO1) depletes tryptophan to dampen anti-tumor T cells, yet IDO1 inhibitors (IDO1i) have failed clinically. Using deep visual proteomics, we isolated IDO1 high, medium and low ovarian tumor cells in situ and found IDO1 tightly linked to interferon-{gamma} (IFN-{gamma}) signaling and heterogeneously expressed. Across orthogonal models with tunable IDO1, IFN-{gamma} killed ovarian cancer via a pathway requiring IFN-{gamma} signaling, IDO1-dependent tryptophan depletion, and a biphasic integrated stress response that initially protects from starvation and later drives death. IDO1i or tryptophan supplementation rescued these effects, promoting tumor survival. These data reveal a context-dependent, tumor-suppressive facet of IDO1 and explain how IDO1i can paradoxically favor cancer viability. Our findings call for re-evaluation of IDO1 as a target and suggest exploiting the tryptophan-starvation/GCN2-ISR axis to enhance therapy.

cancer biology↗

bioRxiv2023

A Back-Door Insights into the modulation of Src kinase activity by the polyamine spermidine

Src is a protein tyrosine kinase commonly activated downstream of transmembrane receptors and plays key roles in cell growth, migration and survival signaling pathways. In conventional dendritic cells (cDCs), Src is involved in the activation of the non-enzymatic functions of indoleamine 2,3-dioxygenase 1 (IDO1), an immunoregulatory molecule endowed with both catalytic activity and signal transducing properties. Prompted by the discovery that the metabolite spermidine confers a tolerogenic phenotype on cDCs that is dependent on both the expression of IDO1 and the activity of Src kinase, we here investigated the spermidine mode of action. We found that spermidine directly binds Src in a previously unknown allosteric site located on the backside of the SH2 domain and thus acts as a positive allosteric modulator of the enzyme. Besides confirming that Src phosphorylates IDO1, here we showed that spermidine promotes the protein-protein interaction of Src with IDO1. Overall, this study may pave the way toward the design of allosteric modulators able to switch on/off the Src-mediated pathways, including those involving the immunoregulatory protein IDO1.

molecular biology↗

bioRxiv2020

Interaction of clinical-stage antibodies with heme predicts physiochemical and functional liabilities relevant for developability

Immunoglobulin repertoires contain a fraction of antibodies that recognize low molecular weight compounds, including some enzymes cofactors, such as heme. Here, by using a set of 113 samples with variable region sequences matching clinical-stage antibodies, we demonstrated that a considerable number of these antibodies interact with heme. Antibodies that interact with heme possess specific sequence traits of their antigen-binding regions. Moreover they manifest particular physicochemical and functional qualities i.e. increased hydrophobicity, higher propensity of self-binding, higher intrinsic polyreactivity and reduced expression yields. Thus, interaction with heme is a strong predictor of different molecular and functional qualities of antibodies. Notably, these qualities are of high importance for therapeutic antibodies, as their presence was associated with failure of drug candidates to reach clinic. Our study reveled an important facet of information about relationship sequence-function in antibodies. It also offers a convenient tool for detection of liabilities of therapeutic antibodies.

immunology↗