Biology subjects

Viiri, K.

Publications and source records attributed to Viiri, K..

8 recordsLinked to original sources

bioRxiv2026

Enterovirus-driven interferon signaling induces epithelial TG2 via JAK-STAT: Implications for the onset of celiac disease

Background & AimsCeliac disease (CeD) is an autoimmune disorder triggered by dietary gluten in genetically predisposed individuals, but environmental factors contributing to disease onset remain incompletely defined. Epidemiological studies implicate enterovirus infections as potential triggers. Here, we investigated the epithelial-intrinsic mechanisms by which coxsackievirus B1 (CVB1) infection may prime the intestine for CeD. MethodsHuman intestinal organoids were infected with CVB1 and analyzed using single-cell RNA sequencing to resolve lineage-specific responses. Interferon signaling and transglutaminase 2 (TG2) regulation were interrogated using type I interferon stimulation and pharmacologic JAK inhibition. ResultsCVB1 infection induced a robust epithelial antiviral program dominated by type I interferon signaling. This response was accompanied by marked upregulation of TG2 expression and enzymatic activity. Single-cell analysis localized TG2 induction to immature goblet-lineage cells, which exhibited strong interferon-stimulated gene activation and epithelial stress signatures. Mechanistically, IFN-/{beta} stimulation was sufficient to induce TG2 via JAK-STAT signaling, while JAK inhibition effectively suppressed both TG2 expression and activity. In parallel, CVB1 infection triggered coordinated mucin remodeling, including induction of MUC5AC, indicating interferon-linked epithelial reprogramming. Notably, these effects occurred independently of immune cell involvement, highlighting a cell-intrinsic pathway. ConclusionOur findings identify a direct epithelial mechanism linking enterovirus infection to TG2 activation via interferon-driven JAK-STAT signaling. This pathway provides a mechanistic bridge between viral infection and gluten peptide modification, a critical step in the onset of CeD. The reversibility of TG2 induction by JAK inhibition suggests a potential strategy to prevent virus-mediated priming of celiac disease.

immunology↗

bioRxiv2026

Scinderin-driven Golgi Actin Remodeling coordinates GLP-1 and insulin secretion to regulate glucose homeostasis

Maintenance of glucose homeostasis requires coordinated hormone secretion from intestinal enteroendocrine cells and pancreatic {beta}-cells, yet the intracellular mechanisms that couple nutrient sensing to endocrine output remain poorly defined. Here, we identify the actin remodeler Scinderin (SCIN) as a shared regulator of hormone secretion across these systems. SCIN is selectively expressed in enteroendocrine L-cells and pancreatic {beta}-cells, where it localizes to phosphatidylinositol-4-phosphate (PI(4)P)-enriched Golgi membranes and controls Golgi-associated actin dynamics. Loss of SCIN disrupts Golgi organization, impairs prohormone trafficking, and reduces secretory granule formation, resulting in defective nutrient-stimulated GLP-1 and insulin secretion while preserving cAMP-dependent amplification pathways. In vivo, tissue-specific deletion of Scin compromises incretin responses, {beta}-cell insulin secretion, and systemic glucose homeostasis. Consistent with these findings, SCIN expression is reduced in human diabetic {beta}-cells and associates with stress-related loss of {beta}-cell maturity. Transcriptomic analyses reveal a conserved Golgi stress program upon SCIN loss, linking intracellular trafficking defects to endocrine dysfunction. Together, our results identify SCIN-dependent Golgi actin remodeling as a rate-limiting intracellular mechanism coordinating enteroendocrine and pancreatic hormone secretion. This work uncovers a shared, targetable node controlling endocrine output, providing a mechanistic link between secretory pathway dysfunction and diabetes.

cell biology↗

bioRxiv2026

Deep Invaginations of Nuclear Envelope Coordinate Spatial Organization of Chromatin in Epithelium

Cell nuclei are often used to assess cell health, but how their shapes vary in normal tissues and how they respond to mechanical forces is not well understood. Here, we describe deep invaginations of the nuclear envelope (DINEs) as common features of epithelial cell nuclei. After their formation, DINEs exist independently of the cytoskeleton, depend on A-type lamins, and emerge in response to cell crowding, contact inhibition, and tissue maturation. High-resolution imaging shows that, in contrast to the peripheral nuclear lamina, DINEs contain densely packed chromatin with regions of active gene transcription. They also remodel dynamically during confined migration, allowing nuclei to adapt to physical constraints. Mechanistically, DINE formation is linked to suppression of MAPK signaling, while activation of growth-promoting pathways reduces their occurrence. These findings reveal DINEs as intrinsic, mechanosensitive structures that coordinate nuclear shape, chromatin organization, and gene activity, providing new insight into how epithelial cells integrate mechanical and biochemical cues to maintain tissue homeostasis. TeaserDeep nuclear envelope invaginations organize chromatin and gene activity in response to epithelial crowding.

cell biology↗

bioRxiv2026

Coxsackievirus B Escapes Antiviral CD8⁺ T Cells but Triggers Robust CD4⁺ Memory Responses

Coxsackieviruses B (CVBs) are plausible triggers of the pancreatic islet autoimmunity leading to type 1 diabetes. Islet autoantibody seroconversion correlates with persistent CVB infections in the gut and pancreas, suggesting defective antiviral control and the need to define immune mechanisms at the intestinal entry site. We investigated how CVB3 modulates antigen presentation, the viral immunopeptidome of enterocytes and antigen-presenting cells, and downstream T-cell immunity. CVB3-infected enterocytes escaped immune recognition by downregulating HLA Class I and viral peptide presentation, impairing CD8+ T-cell responses in vitro. In CVB-seropositive individuals, circulating CVB-reactive CD8+ T cells were stalled in naive-like and exhausted effector/memory states. In contrast, CVB3 induced HLA class II upregulation, promoting robust CD4 T-cell activation. Circulating CVB3-reactive CD4 T cells fully differentiated into polyfunctional T helper memory. These findings indicate that CVB3 antiviral control is predominantly CD4 T-cell-mediated and provide a rationale for mucosal vaccination strategies and immune monitoring tools to follow infection or vaccination. TeaserCoxsackievirus evades CD8+ T-cell immunity in the gut, leaving CD4+ T cells as the main line of antiviral defense.

immunology↗

bioRxiv2021

Maf is a regulator of differentiation for gut immune epithelial cell Microfold cell (M cell)

Microfold cells (M cells) are a specialized subset of epithelial intestinal cells responsible for immunosurveillance of the gastrointestinal tract. M cells are located in the Peyers patches and are crucial for monitoring and the transcytosis of antigens, microorganisms, and pathogens via their mature receptor GP2. A mature M cell with Gp2 receptor aids in the uptake of antigens, which are passed through the single layer of epithelium and presented to underlying antigen-presenting cells and processed further down-stream with B cells, T cells, and dendritic cells. Recent studies revealed several transcription factors and ligands responsible for the development and differentiation of mature M cells however, an exhaustive list of factors remains to be elucidated. Our recent work on the epigenetic regulation of M cell development found 12 critical transcription factors that were controlled by the polycomb recessive complex 2. Musculoaponeurotic fibrosarcoma transcription factor (Maf) was identified as a gene regulated by the polycomb repressive complex (PRC2) during the development of M cells. In this paper, we explore Mafs critical role in M cell differentiation and maturation. Maf falls under the purview of RANKL signaling, is localized in the Peyers patches of the intestine, and is expressed by M cells. Given that, complete knockout of the Maf gene leads to a lethal phenotype, organoids isolated from Maf knockout mice and treated with RANKL exhibited impaired M cell development and a significant decrease in Gp2 expression. These findings reveal that Maf is an important regulator for M cell development and differentiation.

developmental biology↗

bioRxiv2021

Atoh8 is a regulator of intestinal microfold cell (M cell) differentiation

Intestinal microfold cells (M cells) are a dynamic lineage of epithelial cells that initiate mucosal immunity in the intestine. They are responsible for the uptake and transcytosis of microorganisms, pathogens and other antigens in the gastrointestinal tract. A mature M cell expresses a receptor Gp2 which binds to pathogens and aids in the uptake. Due to the rarity of these cells in the intestine, its development and differentiation remains yet to be fully understood. We recently demonstrated that polycomb repressive complex 2 (PRC2) is an epigenetic regulator of M cell development and 12 novel transcription factors including Atoh8 were revealed to be regulated by the PRC2. Here, we show that Atoh8 acts as a regulator of M cell differentiation; absence of Atoh8 led to a significant increase in the number of Gp2+ mature M cells and other M cell associated markers. Atoh8 null mice showed an increase in transcytosis capacity of luminal antigens. Increase in M cell population has been previously reported to be detrimental to mucosal immunity because some pathogens like orally acquired prions have been able to exploit the transcytosis capacity of M cells to infect the host; mouse with increased population of M cells are also susceptible to Salmonella infections. Our study here demonstrates that the population density of intestinal M-cell in the Peyers patch is regulated by the PRC2 regulated Atoh8.

molecular biology↗

bioRxiv2021

JAZF1-SUZ12 dysregulates PRC2 function and gene expression during cell differentiation

Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 (H3K27me3) to maintain repression of genes specific for other cell types and is essential for cell differentiation. In endometrial stromal sarcoma, the PRC2 subunit SUZ12 is often fused with the NuA4/TIP60 subunit JAZF1. Here, we show that JAZF1-SUZ12 dysregulates PRC2 composition, recruitment, histone modification, gene expression and cell differentiation. The loss of the SUZ12 N-terminus in the fusion protein disrupted interaction with the PRC2 accessory factors JARID2, EPOP and PALI1 and prevented recruitment of PRC2 from RNA to chromatin. In undifferentiated cells, JAZF1-SUZ12 occupied PRC2 target genes but gained a JAZF1-like binding profile during cell differentiation. JAZF1-SUZ12 reduced H3K27me3 and increased H4Kac at PRC2 target genes, and this was associated with disruption in gene expression and cell differentiation programs. These results reveal the defects in chromatin regulation caused by JAZF1-SUZ12, which may underlie its role in oncogenesis.

molecular biology↗

bioRxiv2020

Polycomb Repressive Complex 2-controlled Essrg regulates intestinal Microfold cell differentiation.

Microfold cells (M cells) are immunosurveillance epithelial cells located in the Peyers patches in the intestine responsible for monitoring and transcytosis of antigens, microorganisms and pathogens. Many transcription factors, e.g., Spi-B and Sox8, necessary to M cell differentiation have been described but the exhaustive set of factors sufficient for differentiation and development of a mature M cell remains elusive. Moreover, the role of polycomb repressive complex 2 (PRC2) as an epigenetic regulator of M cell development has not yet been interrogated. Here, we show that PRC2 regulates a significant set of genes during the M cell differentiation including many transcription factors. Estrogen related receptor gamma (Esrrg) is a novel M cell specific transcription factor acting on a RankL-Rank induced NF-kB pathway, upstream of Sox8 and necessary but not sufficient for a mature M cell marker Gp2 expression. To conclude, with the aid of PRC2 target survey we identified the list of developmental genes specifically implicated in M cell development and Essrg as a necessary factor for Sox8-mediated M cell differentiation.

molecular biology↗