Biology subjects

Hoover, A.

Publications and source records attributed to Hoover, A..

4 recordsLinked to original sources

bioRxiv2026

FAK Dependent Focal Adhesion Remodeling Drives Arsenical Vesicant Induced Skin Injury

Chemical vesicants cause severe skin injury characterized by inflammation, tissue destruction, and separation of the epidermis from the underlying dermis. However, the molecular mechanisms linking vesicant exposure to the disruption of epidermal adhesion remain poorly understood. Phenylarsine oxide (PAO), a commonly used lewisite analog, is a potent inducer of cutaneous blistering and a strong inhibitor of protein tyrosine phosphatases. Here, we show that PAO rapidly induces focal adhesion kinase (FAK) phosphorylation and downstream signaling in epidermal keratinocytes, accompanied by accelerated focal adhesion disassembly and molecular turnover. Genetic ablation of FAK stabilizes focal adhesions and markedly suppresses PAO-induced adhesion remodeling. Importantly, epidermal-specific deletion of FAK protects mouse skin from PAO-induced microvesication, inflammatory responses, and cell death. Pharmacological inhibition of FAK similarly preserves focal adhesion stability in vitro and attenuates PAO-induced skin injury in vivo, phenocopying the protective effects of genetic FAK deficiency. Together, our findings identify aberrant FAK activation as a critical signaling event linking arsenical vesicant exposure to focal adhesion failure and skin vesication, and suggest that targeting FAK may provide a therapeutic strategy to mitigate chemical vesicant-induced skin injury.

cell biology↗

bioRxiv2026

A proteomic atlas of organelle remodeling identifies lysosomal SNX3 as a regulator of Notch signaling in epidermal differentiation

Differentiation of epidermal keratinocytes is accompanied by profound reorganization of intracellular architecture, but how organelle remodeling interfaces with cell fate control is not well understood. Here, we generate a compartment-resolved proteomic map of keratinocyte differentiation and identify extensive remodeling of lysosomes, mitochondria, autophagic vesicles, plasma membrane, and nucleus. Differentiating keratinocytes display coordinated enrichment of lysosomal degradative machinery, vesicular trafficking factors, and mitochondrial metabolic proteins, revealing organelle remodeling as a prominent feature of epidermal differentiation. From the lysosomal proteome, we identify Sorting Nexin 3 (SNX3) as a critical regulator of epidermal homeostasis. SNX3 increasingly localizes to LAMP1-positive vesicles during differentiation, and its loss impairs epidermal differentiation, suppresses Notch signaling, and promotes proliferative gene expression. In vivo, SNX3-deficient skin grafts fail to maintain normal epidermal architecture and instead develop into squamous cell carcinoma. Mechanistically, SNX3 mediates efficient Notch receptor activation, as SNX3 loss reduces nuclear Notch1 and NICD production, whereas NICD re-expression can rescue the differentiation defect. Our study defines a proteomic framework for organelle remodeling during epidermal differentiation and identifies lysosome-associated SNX3 as a key link between endolysosomal trafficking, Notch signaling, and epidermal tissue homeostasis.

cell biology↗

bioRxiv2019

Factors that influence the thymic selection of CD8αα intraepithelial lymphocytes

Thymocytes bearing {beta} T cell receptors (TCR{beta}) with high affinity for self-peptide-MHC complexes undergo negative selection or are diverted to alternate T cell lineages, a process termed agonist selection. Among thymocytes bearing TCRs restricted to MHC class I, agonist selection can lead to the development of precursors that can home to the gut and give rise to CD8-expressing intraepithelial lymphocytes (CD8 IELs). The factors that influence the choice between negative selection versus CD8 IEL development remain largely unknown. Using a synchronized thymic tissue slice model that supports both negative selection and CD8IEL development, we show that the affinity threshold for CD8 IEL development is higher than for negative selection. We also investigate the impact of peptide presenting cells and cytokines, and the migration patterns associated with these alternative cell fates. Our data highlight the roles of TCR affinity and the thymic microenvironments on T cell fate.

immunology↗

bioRxiv2019

A role for phagocytosis in inducing cell death during thymocyte negative selection

Autoreactive thymocytes are eliminated during negative selection in the thymus, a process important for establishing self-tolerance. Thymic phagocytes serve to remove dead thymocytes, but whether they play additional roles during negative selection remains unclear. Here, we demonstrate that phagocytosis promotes negative selection, and that negative selection is more efficient when the phagocyte also presents the negative selecting peptide. Our findings support a two-step model for negative selection in which thymocytes initiate the death process following strong TCR signaling, but ultimately depend upon phagocytosis for their timely death. Thus, the phagocytic capability of cells that present self-peptides is a key determinant of thymocyte fate.

immunology↗