Biology subjects

Laiho, J. E.

Publications and source records attributed to Laiho, J. E..

3 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↗

bioRxiv2018

Detection of enterovirus protein and RNA in multiple tissues from nPOD organ donors with type 1 diabetes

Epidemiological studies have shown an association between enterovirus (EV) infections and type 1 diabetes (T1D), and EV protein has been detected in the pancreatic islets of T1D patients. Here we correlated the detection of EVs in lymphoid tissues (spleen and pancreatic lymph nodes) and small intestinal mucosa to the virus detection in the pancreas of T1D, autoantibody-positive (aab+) and non-diabetic control organ donors of the Network for Pancreatic Organ Donors with Diabetes (nPOD) study. Formalin-fixed paraffin-embedded tissue samples were screened for insulin and EV protein using immunohistochemistry, and frozen tissue for EV genome using RT-PCR. The presence of EV protein in the pancreatic islets correlated with the presence of insulin-positive cells. Altogether 62 % of T1D and aab+ donors were positive for EV protein in pancreatic islets (only insulin-positive donors included), 40 % in duodenum and 32 % in spleen, compared to 33 %, 14 %, and 27 % of non-diabetic controls. Pancreatic lymph nodes were positive for EV protein in 60 % of T1D and aab+ cases. T1D and aab+ donors were more frequently VP1-positive in multiple organs than control donors (39 % vs. 11 %; including only insulin-positive donors). EV RNA was found in selected donors and from multiple tissue types except for duodenum, and individual T1D and aab+ donors were EV RNA-positive in multiple organs. The role of extra-pancreatic organs and their interplay with EV in T1D pathogenesis remains to be solved, but we hypothesize that these organs may serve as a reservoir for the virus which may reside in these tissues in a slow-replicating persistent form.

epidemiology↗