Biology subjects

Aziz, Z.

Publications and source records attributed to Aziz, Z..

3 recordsLinked to original sources

bioRxiv2025

Trsp is required by regulatory T cells to prevent lethal autoimmunity in mice

Selenoproteins are involved in immune cell metabolism, yet the roles of these proteins in T cell development and function remain largely unknown. The Trsp gene encodes the selenocysteine tRNA (tRNASec) required for translation of all selenoproteins. In this study, we found that Trsp was required for thymopoiesis, with the majority of tRNASec-deficient T cells not progressing beyond double negative 3 stage, with egressed thymocytes undergoing peripheral homeostatic expansion. Trsp-deficient CD4+ T cells exhibited impairments in TCR and IL-2 signaling and did not cause inflammation in experimental models. On the other hand, Trsp-deficient regulatory T (Treg) cells exhibited defects in suppressive function ex vivo and Treg-specific Trsp deletion using Trspfl/flFoxp3YFP-Cre (Trsp!{iota}Treg) mice caused fatal autoimmunity similar to FOXP3-deficient mice. Reducing oxidative stress via 2-HOBA administration prolonged survival in these Trsp!{iota}Treg mice. These findings indicate that tRNASec is required for T cell homeostasis and may be therapeutic targets in inflammation. One sentence summaryTrsp, a gene required for translation of all selenoproteins, is essential for all T cell development and function, especially regulatory T cells.

immunology↗

bioRxiv2024

Nematode Extracellular Protein Interactome Expands Connections between Signaling Pathways

Multicellularity was accompanied by the emergence of new classes of cell surface and secreted proteins. The nematode C. elegans is a favorable model to study cell surface interactomes, given its well-defined and stereotyped cell types and intercellular contacts. Here we report our C. elegans extracellular interactome dataset, the largest yet for an invertebrate. Most of these interactions were unknown, despite recent datasets for flies and humans, as our collection contains a larger selection of protein families. We uncover new interactions for all four major axon guidance pathways, including ectodomain interactions between three of the pathways. We demonstrate that a protein family known to maintain axon locations are secreted receptors for insulins. We reveal novel interactions of cystine-knot proteins with putative signaling receptors, which may extend the study of neurotrophins and growth-factor-mediated functions to nematodes. Finally, our dataset provides insights into human disease mechanisms and how extracellular interactions may help establish connectomes.

biochemistry↗

bioRxiv2023

Eosinophils exert direct and indirect anti-tumorigenic effects in the development of esophageal squamous cell carcinoma

Background/AimsEosinophils are present in several solid tumors and have context-dependent function. Our aim is to define the contribution of eosinophils in esophageal squamous cell carcinoma (ESCC), since their role in ESCC is unknown. MethodsEosinophils were enumerated in tissues from two ESCC cohorts. Mice were treated with 4-nitroquinolone-1-oxide (4-NQO) for 8 weeks to induce pre-cancer or 16 weeks to induce carcinoma. Eosinophil number was modified by monoclonal antibody to IL-5 (IL5mAb), recombinant IL-5 (rIL-5), or genetically with eosinophil-deficient ({Delta}dblGATA) mice or mice deficient in eosinophil chemoattractant eotaxin-1 (Ccl11-/-). Esophageal tissue and eosinophil specific RNA-sequencing was performed to understand eosinophil function. 3-D co-culturing of eosinophils with pre-cancer or cancer cells was done to ascertain direct effects of eosinophils. ResultsActivated eosinophils are present in higher numbers in early stage versus late stage ESCC. Mice treated with 4-NQO exhibit more esophageal eosinophils in pre-cancer versus cancer. Correspondingly, epithelial cell Ccl11 expression is higher in mice with pre-cancer. Eosinophil depletion using three mouse models (Ccl11-/- mice, {Delta}dblGATA mice, IL5mAb treatment) all display exacerbated 4-NQO tumorigenesis. Conversely, treatment with rIL-5 increases esophageal eosinophilia and protects against pre-cancer and carcinoma. Tissue and eosinophil RNA-sequencing revealed eosinophils drive oxidative stress in pre-cancer. In vitro co-culturing of eosinophils with pre-cancer or cancer cells resulted in increased apoptosis in the presence of a degranulating agent, which is reversed with N-acetylcysteine, a reactive oxygen species (ROS) scavenger. {Delta}dblGATA mice exhibited increased CD4 T cell infiltration, IL-17, and enrichment of IL-17 pro-tumorigenic pathways. ConclusionEosinophils likely protect against ESCC through ROS release during degranulation and suppression of IL-17.

cancer biology↗