Biology subjects

Hunter, C. S.

Publications and source records attributed to Hunter, C. S..

3 recordsLinked to original sources

bioRxiv2026

ER Stress-Induced beta-Cell Apoptosis is Linked to Novel Select Lipid Signaling at the Transcriptional Level: Implications in T1D Development

Type 1 diabetes (T1D) is a consequence of {beta}-cell death. ER stress precedes T1D onset and prolonged ER stress in {beta}-cells can lead to {beta}-cell apoptosis. We reported that lipid signaling generated by the Ca2+-independent phospholipase A2{beta} (iPLA2{beta}), encoded by Pla2g6, participates in ER stress-mediated {beta}-cell apoptosis. {beta}-Cell membranes are enriched in arachidonic acid containing glycerophospholipids and the iPLA2{beta} catalyzes the hydrolysis of arachidonic acid in ER stressed {beta}-cells. Metabolism of arachidonic acid leads to the generation of various proinflammatory lipids, raising the possibility that they contribute to ER stress and {beta}-cell death leading to T1D. However, molecular mechanisms by which such {beta}-cell-iPLA2{beta}-derived lipid (iDL) signaling contributes to {beta}-cell apoptosis are not understood. It is well known that ER stress-mediated {beta}-cell apoptosis is associated with induction of transcription factors, NF{kappa}B and STAT1. We report here that both induce Pla2g6 and, unexpectedly, we find that iPLA2{beta}, which lacks DNA-binding motifs, associates with NFkB, Stat1, and Pla2g6 promoter regions. Consistently, p65-NF{kappa}B and pSTAT1 induction is reduced with select inhibition or knockdown of iPLA2{beta}. Surprisingly, iPLA2{beta} expression is also reduced by select inhibition of iPLA2{beta}, raising the possibility of feedback regulation by iDLs. In support, we find that select iDLs, recognized to be proinflammatory, enhance association of iPLA2{beta} with Pla2g6, Nfkb, and Stat1 promoter regions leading to induction of all three gene products and {beta}-cell apoptosis. Our findings reveal previously unrecognized transcriptional regulation by iDL signaling and, iPLA2{beta} itself, that leads to gene products that promote {beta}-cell apoptosis. Analogous findings in human islets validate this mechanism raising the possibility that targeting select lipid signaling can reduce ER stress in {beta}-cells and ameliorate T1D development.

cell biology↗

bioRxiv2025

Tomosyn-2 Regulates Postnatal β-Cell Expansion and Insulin Secretion to Maintain Glucose Homeostasis.

The transition from proliferative to functionally mature {beta}-cells is a critical developmental process, yet the molecular mechanisms that coordinate this shift remain poorly understood. Here, we identify Tomosyn-2 as a key regulator of {beta}-cell maturation. Tomosyn-2 expression declines with age in mouse islets, coinciding with enhanced biphasic glucose-stimulated insulin secretion (GSIS) and reduced {beta}-cell proliferation. Genetic deletion of Tomosyn-2 improves glucose tolerance, elevates plasma insulin levels, and augments islet insulin secretion, without altering systemic insulin sensitivity. Mechanistically, Tomosyn-2 interacts with syntaxin-1A (Stx1A) to inhibit insulin granule exocytosis by limiting SNARE complex formation. Transcriptomic and network analyses reveal that Tomosyn-2 loss reprograms gene expression to strengthen the coupling between insulin secretion and proliferative pathways. Its deletion also reduces {beta}-cell proliferation and mass expansion, suppresses cell cycle and Akt1 signaling, and promotes {beta}-cell identity, maturation, and altered islet architecture. These findings identify Tomosyn-2 as a crucial molecular switch that orchestrates the balance between proliferation and functional maturation during postnatal {beta}-cell development.

cell biology↗

bioRxiv2022

ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression

The role of aberrant glycosylation in pancreatic ductal adenocarcinoma (PDAC) remains an under-investigated area of research. In this study, we determined that the ST6GAL1 sialyltransferase, which adds 2,6-linked sialic acids to N-glycosylated proteins, is upregulated in patients with early-stage PDAC, and further increased in advanced disease. A tumor-promoting function for ST6GAL1 was elucidated using tumor xenograft models with human PDAC cells. Additionally, we developed a genetically-engineered mouse (GEM) with transgenic expression of ST6GAL1 in the pancreas, and found that mice with dual expression of ST6GAL1 and oncogenic KRASG12D have greatly accelerated PDAC progression and mortality compared with mice expressing KRASG12D alone. As ST6GAL1 imparts progenitor-like characteristics, we interrogated ST6GAL1s role in acinar to ductal metaplasia (ADM), a process that fosters neoplasia by reprogramming acinar cells into ductal, progenitor-like cells. We confirmed that ST6GAL1 promotes ADM using multiple models including the 266-6 cell line, GEM-derived organoids and tissues, and an in vivo model of inflammation-induced ADM. EGFR is a key driver of ADM and is known to be activated by ST6GAL1-mediated sialylation. Importantly, EGFR activation was dramatically increased in acinar cells and organoids from mice with transgenic ST6GAL1 expression. These collective results highlight a novel glycosylation-dependent mechanism involved in early stages of pancreatic neoplasia.

cancer biology↗