A novel membrane protein Hoka regulates septate junction organization and stem cell homeostasis in the Drosophila gut

AbstractSmooth septate junctions (sSJs) regulate the paracellular transport in the intestinal and renal system in arthropods. In Drosophila, the organization and physiological function of sSJs are regulated by at least three sSJ-specific membrane proteins: Ssk, Mesh, and Tsp2A. Here, we report a novel sSJ membrane protein Hoka, which has a single membrane-spanning segment with a short extracellular region having 13-amino acids, and a cytoplasmic region with three repeats of the Tyr-Thr-Pro-Ala motif. The larval midgut in hoka-mutants shows a defect in sSJ structure. Hoka forms a complex with Ssk, Mesh, and Tsp2A and is required for the correct localization of these proteins to sSJs. Knockdown of hoka in the adult midgut leads to intestinal barrier dysfunction, stem cell overproliferation, and epithelial tumors. In hoka-knockdown midguts, aPKC is up-regulated in the cytoplasm and the apical membrane of epithelial cells. The depletion of aPKC and yki in hoka-knockdown midguts results in reduced stem cell overproliferation. These findings indicate that Hoka cooperates with the sSJ-proteins Ssk, Mesh, and Tsp2A to organize sSJs, and is required for maintaining intestinal stem cell homeostasis through the regulation of aPKC and Yki activities in the Drosophila midgut.Summary statementDepletion of hoka, a gene encoding a novel septate junction protein, from the Drosophila midgut results in the disruption of septate junctions, intestinal barrier dysfunction, stem cell overproliferation, and epithelial tumors.

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The novel membrane protein Hoka regulates septate junction organization and stem cell homeostasis in the Drosophila gut

Journal of Cell Science ◽

10.1242/jcs.257022 ◽

2021 ◽

Vol 134 (6) ◽

Author(s):

Yasushi Izumi ◽

Kyoko Furuse ◽

Mikio Furuse

Keyword(s):

Stem Cell ◽

Membrane Protein ◽

Intestinal Barrier ◽

Septate Junction ◽

The Novel ◽

Barrier Dysfunction ◽

Cell Homeostasis ◽

Extracellular Region ◽

Membrane Spanning ◽

Specific Membrane

ABSTRACT Smooth septate junctions (sSJs) regulate the paracellular transport in the intestinal tract in arthropods. In Drosophila, the organization and physiological function of sSJs are regulated by at least three sSJ-specific membrane proteins: Ssk, Mesh and Tsp2A. Here, we report a novel sSJ membrane protein, Hoka, which has a single membrane-spanning segment with a short extracellular region, and a cytoplasmic region with Tyr-Thr-Pro-Ala motifs. The larval midgut in hoka mutants shows a defect in sSJ structure. Hoka forms a complex with Ssk, Mesh and Tsp2A, and is required for the correct localization of these proteins to sSJs. Knockdown of hoka in the adult midgut leads to intestinal barrier dysfunction and stem cell overproliferation. In hoka-knockdown midguts, aPKC is upregulated in the cytoplasm and the apical membrane of epithelial cells. The depletion of aPKC and yki in hoka-knockdown midguts results in reduced stem cell overproliferation. These findings indicate that Hoka cooperates with the sSJ proteins Ssk, Mesh and Tsp2A to organize sSJs, and is required for maintaining intestinal stem cell homeostasis through the regulation of aPKC and Yki activities in the Drosophila midgut.

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Septate junctions regulate gut homeostasis through regulation of stem cell proliferation and enterocyte behavior in Drosophila

10.1101/582148 ◽

2019 ◽

Author(s):

Yasushi Izumi ◽

Kyoko Furuse ◽

Mikio Furuse

Keyword(s):

Cell Proliferation ◽

Stem Cell ◽

Intestinal Barrier ◽

Septate Junction ◽

Intestinal Barrier Function ◽

Barrier Dysfunction ◽

Septate Junctions ◽

Stem Cell Proliferation ◽

Associated Proteins ◽

Intestinal Hypertrophy

AbstractSmooth septate junctions (sSJs) contribute to the epithelial barrier, which restricts leakage of solutes through the paracellular route of epithelial cells in the Drosophila midgut. We previously identified three sSJ-associated membrane proteins, Ssk, Mesh, and Tsp2A, and showed that these proteins were required for sSJ formation and intestinal barrier function in the larval midgut. Here, we investigated the roles of sSJs in the Drosophila adult midgut. Depletion of any of the sSJ-proteins from enterocytes resulted in remarkably shortened lifespan and intestinal barrier dysfunction in flies. Interestingly, the sSJ protein-deficient flies showed intestinal hypertrophy accompanied by accumulation of morphologically abnormal enterocytes. The phenotype was associated with increased stem cell proliferation and activation of the MAP kinase and Jak-Stat pathways in stem cells. Loss of cytokines Unpaired2 and Unpaired3, which are involved in Jak-Stat pathway activation, suppressed the intestinal hypertrophy, but not the increased stem cell proliferation, in flies lacking Mesh. The present findings suggest that SJs play a crucial role in maintaining tissue homeostasis through regulation of stem cell proliferation and enterocyte behavior in the Drosophila adult midgut.Summary statementDepletion of smooth septate junction-associated proteins from enterocytes in the Drosophila adult midgut results in intestinal hypertrophy accompanied by accumulation of morphologically aberrant enterocytes and increased stem cell proliferation.

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Chronic stress and intestinal barrier dysfunction: Glucocorticoid receptor and transcription repressor HES1 regulate tight junction protein Claudin-1 promoter

Scientific Reports ◽

10.1038/s41598-017-04755-w ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 24

Author(s):

Gen Zheng ◽

Gordon Victor Fon ◽

Walter Meixner ◽

Amy Creekmore ◽

Ye Zong ◽

...

Keyword(s):

Glucocorticoid Receptor ◽

Tight Junction ◽

Chronic Stress ◽

Intestinal Barrier ◽

Tight Junction Protein ◽

Barrier Dysfunction ◽

Intestinal Barrier Dysfunction ◽

Junction Protein

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Asymptomatic Hyperamylasemia in Stevens-Johnson Syndrome Is Associated with Intestinal Barrier Dysfunction

BioMed Research International ◽

10.1155/2020/3531907 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Yujen Tseng ◽

Zhongguang Luo ◽

Hongyang Zhang ◽

Chengfeng Zhang ◽

Jian Chen

Keyword(s):

Serum Amylase ◽

Intestinal Barrier ◽

Stevens Johnson Syndrome ◽

Fecal Occult Blood ◽

Study Cohort ◽

Barrier Dysfunction ◽

Intestinal Barrier Dysfunction ◽

Johnson Syndrome ◽

Junction Protein ◽

Clinical Awareness

Background/Objectives. Stevens-Johnson syndrome (SJS) is an allergic disease characterized by extensive epidermal detachment and mucositis. SJS involves both the skin and mucosal membranes, including the gastrointestinal tract. The present study is aimed at understanding the underlying reason of asymptomatic hyperamylasemia in patients with SJS, which may be associated with mucosal injury of the GI tract. Methods. A retrospective study on SJS patients was conducted at a tertiary medical center. All patients diagnosed as SJS, with available serum amylase index, were included. Clinical data of all subjects were retrospectively collected and analyzed. Colonic mucosal biopsies were obtained to measure tight junction protein expression. Results. A total of nine patients were included in the present study for study analysis. The average serum amylase of the study cohort was 228.78 ± 204.18 U / L . Among which, five patients had a positive fecal occult blood test (FOBT). Colonic mucosal biopsies were obtained and stained with occludin and zonula occludens-1 (ZO-1). The expression of occludin and ZO-1 was significantly downregulated in SJS patients ( p < 0.01 ), which was indicative of intestinal barrier dysfunction. Conclusion. Hyperamylasemia often extends beyond pancreatic diseases. Clinical awareness of asymptomatic hyperamylasemia secondary to other systemic diseases can help avoid unnecessary overexamination and overtreatment.

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Intestinal Barrier Dysfunction Exacerbates Neuroinflammation via the TLR4 Pathway in Mice With Heart Failure

Frontiers in Physiology ◽

10.3389/fphys.2021.712338 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jun-Yu Huo ◽

Wan-Ying Jiang ◽

Ting Yin ◽

Hai Xu ◽

Yi-Ting Lyu ◽

...

Keyword(s):

Heart Failure ◽

Intestinal Permeability ◽

Intestinal Barrier ◽

Sham Operation ◽

Barrier Dysfunction ◽

Intestinal Alkaline Phosphatase ◽

Intestinal Barrier Dysfunction ◽

Junction Protein ◽

Elevated Expression ◽

The Brain

AimsThe present study aimed to investigate alterations in neuroinflammation after heart failure (HF) and explore the potential mechanisms.MethodsMale wild-type (WT) and Toll-like receptor 4 (TLR4)-knockout (KO) mice were subjected to sham operation or ligation of the left anterior descending coronary artery to induce HF. 8 weeks later, cardiac functions were analyzed by echocardiography, and intestinal barrier functions were examined by measuring tight junction protein expression, intestinal permeability and plasma metabolite levels. Alterations in neuroinflammation in the brain were examined by measuring microglial activation, inflammatory cytokine levels and the proinflammatory signaling pathway. The intestinal barrier protector intestinal alkaline phosphatase (IAP) and intestinal homeostasis inhibitor L-phenylalanine (L-Phe) were used to examine the relationship between intestinal barrier dysfunction and neuroinflammation in mice with HF.ResultsEight weeks later, WT mice with HF displayed obvious increases in intestinal permeability and plasma lipopolysaccharide (LPS) levels, which were accompanied by elevated expression of TLR4 in the brain and enhanced neuroinflammation. Treatment with the intestinal barrier protector IAP significantly attenuated neuroinflammation after HF while effectively increasing plasma LPS levels. TLR4-KO mice showed significant improvements in HF-induced neuroinflammation, which was not markedly affected by intestinal barrier inhibitors or protectors.ConclusionHF could induce intestinal barrier dysfunction and increase gut-to-blood translocation of LPS, which could further promote neuroinflammation through the TLR4 pathway.

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