Analysis of the ‘angulin’ proteins LSR, ILDR1 and ILDR2 – tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis

Higashi, Tomohito; Tokuda, Shinsaku; Kitajiri, Shin‐ichiro; Masuda, Sayuri; Nakamura, Hiroki; Oda, Yusuke; Furuse, Mikio

doi:10.1242/jcs.138271

Cited by 101 publications

(94 citation statements)

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“…Consistent with this concept, actin-dependent, ACE2/spike fusion events proceed from "finger-like" projections and synapses between cells to fusion pore dilation and membrane collapse, closely resembling the orderly biogenesis of myoblast-derived syncytia (Chen et al, 2008;Duan et al, 2018;Kim and Chen, 2019;Shi et al, 2017;Shilagardi et al, 2013). Second, we highlight the remarkable similarities between SARS-CoV-2 spike and tricellular tight junction proteins (Higashi et al, 2013;Oda et al, 2020;Sohet et al, 2015), specifically with respect to membrane-anchoring cysteines and aromatics (Figure 5H; Figure 5-figure supplement 1D,E). These observations suggest that both pathological viruses and adherent cells independently evolved proteins with abnormally strong affinity for the plasma membrane to ensure stability of transcellular complexes (Figure 7H), whether to initiate fusion or maintain tissue integrity.…”

Section: Discussionmentioning

confidence: 90%

“…Of the thousands of human transmembrane proteins, only 15 were "spike-like", featuring both high membrane-proximal cysteine and aromatic content (Figure 5H; Supplementary File 3). Remarkably, the top four are all critical to forming specific types of adhesion junctions: three to tricellular tight junctions (ILDR1, ILDR2, LSR) and one to kidney/intestine tight junctions (IGSF5) (Figure 5-figure supplement 1D) (Higashi et al, 2013;Hirabayashi et al, 2003). In light of the important role for palmitoylation in tricellular tight junction assembly (Oda et al, 2020), these findings suggest that SARS-CoV-2 may operate by a similar mechanism to promote adhesion and transcellular interfaces, an exciting possibility to be explored in future studies.…”

Section: Highly Unusual Membrane-proximal Regions Of Spike Are Needed For Fusionmentioning

confidence: 99%

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SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation

Sanders

Jumper

Ackerman

et al. 2021

eLife

179

178

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Many enveloped viruses induce multinucleated cells (syncytia), reflective of membrane fusion events caused by the same machinery that underlies viral entry. These syncytia are thought to facilitate replication and evasion of the host immune response. Here, we report that co-culture of human cells expressing the receptor ACE2 with cells expressing SARS-CoV-2 spike, results in synapse-like intercellular contacts that initiate cell-cell fusion, producing syncytia resembling those we identify in lungs of COVID-19 patients. To assess the mechanism of spike/ACE2-driven membrane fusion, we developed a microscopy-based, cell-cell fusion assay to screen ~6000 drugs and >30 spike variants. Together with quantitative cell biology approaches, the screen reveals an essential role for biophysical aspects of the membrane, particularly cholesterol-rich regions, in spike-mediated fusion, which extends to replication-competent SARS-CoV-2 isolates. Our findings potentially provide a molecular basis for positive outcomes reported in COVID-19 patients taking statins and suggest new strategies for therapeutics targeting the membrane of SARS-CoV-2 and other fusogenic viruses.

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Section: Discussionmentioning

confidence: 90%

Section: Highly Unusual Membrane-proximal Regions Of Spike Are Needed For Fusionmentioning

confidence: 99%

SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation

Sanders

Jumper

Ackerman

et al. 2021

eLife

179

178

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“…Transepithelial resistance (TER) measurements were performed with a Millicell-ERS electrical resistance meter (Merck KGaA) (22) immediately prior to and following the addition of AG1478 (0, 0.5 and 2 µM) at given time points (24, 48 and 72 h). Resistance (ΔTER) of the HSC-3 layers was calculated as the mean resistance of control inserts (without cells, n≥4) subtracted from the mean resistance of cells treated with various concentrations of AG1478 at given time points (results were representative of ≥4 experiments).…”

Section: Methodsmentioning

confidence: 99%

Changes in cell junctions induced by inhibition of epidermal growth factor receptor in oral squamous cell carcinoma cells

Kakei

Teraoka

Akashi

et al. 2017

Experimental and Therapeutic Medicine

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The benefits of epidermal growth factor receptor (EGFR) targeting in the treatment of head and neck cancer, have been documented. However, a minority of patients with head and neck cancer are unresponsive to EGFR targeting therapies. The present study evaluated the effects and limitations of an EGFR inhibitor on oral squamous cell carcinoma cells, particularly on cell-cell junctions mediated by epithelial (E)-cadherin. HSC-3 oral squamous cell carcinoma cells were treated with the EGFR inhibitor, AG1478 (0, 0.5, 2, 10 and 50 µM), and the effects of EGFR inhibition in HSC-3 cells were evaluated by wound healing assays, E-cadherin immunostaining and measurement of transepithelial electrical resistance in vitro. It was observed that treatment of oral squamous cell carcinoma cells with AG1478 suppressed cell motility, altered cell morphology and increased the number of cell-cell junctions compared with untreated control cells. Knockdown of EGFR induced a similar phenotype to that observed by the inhibition of EGFR. Furthermore, in oral squamous cell carcinoma cells treated with high-dose EGFR inhibitor (50 µM), the small number of cells that survived formed cell-cell junctions that were positive for E-cadherin expression. In cells treated with low concentrations of EGFR inhibitor (2 µM), recovery of epithelial properties was observed. The retention of E-cadherin expression in cells that survived high-dose EGFR inhibitor treatment may be a survival mechanism of cancer cells.

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“…A specialized site of the TJ where macromolecules can pass has been identified to be the tricellular TJ (tTJ), the location where three cells meet [27]. The proteins of the tTJ are tricellulin [28], and three singe-transmembrane proteins, angulin-1 to -3 [29]. The tTJ is virtually impermeable at high tricellulin expression for macromolecules but becomes permeable for it at low expression as observed in the inflammatory bowel disease ulcerative colitis [30].…”

Section: Adherens Junctions and Tight Junctionsmentioning

confidence: 99%

Super-Resolution Imaging of Tight and Adherens Junctions: Challenges and Open Questions

Gonschior

Haucke

Lehmann

2020

IJMS

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The tight junction (TJ) and the adherens junction (AJ) bridge the paracellular cleft of epithelial and endothelial cells. In addition to their role as protective barriers against bacteria and their toxins they maintain ion homeostasis, cell polarity, and mechano-sensing. Their functional loss leads to pathological changes such as tissue inflammation, ion imbalance, and cancer. To better understand the consequences of such malfunctions, the junctional nanoarchitecture is of great importance since it remains so far largely unresolved, mainly because of major difficulties in dynamically imaging these structures at sufficient resolution and with molecular precision. The rapid development of super-resolution imaging techniques ranging from structured illumination microscopy (SIM), stimulated emission depletion (STED) microscopy, and single molecule localization microscopy (SMLM) has now enabled molecular imaging of biological specimens from cells to tissues with nanometer resolution. Here we summarize these techniques and their application to the dissection of the nanoscale molecular architecture of TJs and AJs. We propose that super-resolution imaging together with advances in genome engineering and functional analyses approaches will create a leap in our understanding of the composition, assembly, and function of TJs and AJs at the nanoscale and, thereby, enable a mechanistic understanding of their dysfunction in disease.

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Analysis of the ‘angulin’ proteins LSR, ILDR1 and ILDR2 – tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis

Abstract: There are mistakes in the notation of a mutant protein. All instances of R89Q (including in the figures) should in fact be R97Q.

Cited by 101 publications

References 0 publications

SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation

SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation

Changes in cell junctions induced by inhibition of epidermal growth factor receptor in oral squamous cell carcinoma cells

Super-Resolution Imaging of Tight and Adherens Junctions: Challenges and Open Questions

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