ZO-2 favors Hippo signaling, and its re-expression in the steatotic liver by AMPK restores junctional sealing

González-González, Laura; Gallego-Gutiérrez, Helios; Martín-Tapia, Dolores; Avelino-Cruz, José Everardo; Hernández-Guzmán, Christian; Rangel-Guerrero, Sergio Israel; Álvarez-Salas, Luis Marat; Garay, Erika; Chávez‐Munguía, Bibiana; Gutiérrez‐Ruiz, María Concepción; Hernández-Melchor, Dinorah; López-Bayghen, Esther; González‐Mariscal, Lorenza

doi:10.1080/21688370.2021.1994351

Cited by 9 publications

(2 citation statements)

References 88 publications

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“…This result aligns to our previous observations showing that in the absence of ZO-2, YAP concentrates at the nucleus in both confluent and sparse cultures [ 43 ]. ZO-2 associates to the Hippo pathway kinase LATS, promoting its activation and cell border recruitment [ 65 ]. LATS phosphorylates YAP, and this phosphorylation allows YAP sequestration in the cytoplasm by 14.3.3 protein, in consequence blocking YAP nuclear importation [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

The Role of ZO-2 in Modulating JAM-A and γ-Actin Junctional Recruitment, Apical Membrane and Tight Junction Tension, and Cell Response to Substrate Stiffness and Topography

Pinto-Dueñas,

Hernández-Guzmán,

Marsch

et al. 2024

IJMS

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This work analyzes the role of the tight junction (TJ) protein ZO-2 on mechanosensation. We found that the lack of ZO-2 reduced apical membrane rigidity measured with atomic force microscopy, inhibited the association of γ-actin and JAM-A to the cell border, and instead facilitated p114RhoGEF and afadin accumulation at the junction, leading to an enhanced mechanical tension at the TJ measured by FRET, with a ZO-1 tension probe, and increased tricellular TJ tension. Simultaneously, adherens junction tension measured with an E-cadherin probe was unaltered. The stability of JAM-A and ZO-2 binding was assessed by a collaborative in silico study. The absence of ZO-2 also impacted the cell response to the substrate, as monolayers plated in 20 kPa hydrogels developed holes not seen in parental cultures and displayed a retarded elongation and formation of cell aggregates. The absence of ZO-2 was sufficient to induce YAP and Snail nuclear accumulation in cells cultured over glass, but when ZO-2 KD cells were plated in nanostructured ridge arrays, they displayed an increased abundance of nuclear Snail and conspicuous internalization of claudin-4. These results indicate that the absence of ZO-2 also impairs the response of cells to substrate stiffness and exacerbates transformation triggered by substrate topography.

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Section: Discussionmentioning

confidence: 99%

The Role of ZO-2 in Modulating JAM-A and γ-Actin Junctional Recruitment, Apical Membrane and Tight Junction Tension, and Cell Response to Substrate Stiffness and Topography

Pinto-Dueñas,

Hernández-Guzmán,

Marsch

et al. 2024

IJMS

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“…ZO-2 also maintains the nuclear shape due to its interaction with proteins like lamin B and SUN-1 that link the nucleoskeleton to the cytoskeleton [ 12 ]. ZO-2 also regulates cell size [ 8 ] by acting as a platform of the Hippo pathway [ 8 , 13 ]. ZO-2 is a target of viral oncoproteins, including v-Src [ 14 , 15 ], the E4 region-encoded (E4-ORF1) of adenovirus type 9 that induces the aberrant sequestration of ZO-2 in the cytoplasm [ 16 ], and the E6 protein from high-risk human papillomavirus that delocalizes ZO-2 from the membrane to the cytoplasm and nucleus and stabilizes ZO-2 expression [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Polyubiquitination and SUMOylation Sites Regulate the Stability of ZO-2 Protein and the Sealing of Tight Junctions

Cano-Cortina

Alarcón

Miranda

et al. 2022

Cells

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Tight junctions (TJs) regulate the transit of ions and molecules through the paracellular pathway in epithelial cells. Zonula occludens 2 (ZO-2) is a cytoplasmic TJ protein. Here, we studied the ubiquitination of hZO-2 employing mutants of SUMOylation site K730 present in the GuK domain and the putative ubiquitination residues K759 and K992 located at the GuK domain and proline-rich region, respectively. In immunoprecipitation experiments done with MDCK cells transfected with wild-type (WT) hZO-2 or the ubiquitination-site mutants hZO-2-K759R or -K992R, we observed diminished ubiquitination of the mutants, indicating that residues K759 and K992 in hZO-2 are acceptors for ubiquitination. Moreover, using TUBES, we found that residues K759 and K992 of hZO-2 are targets of K48 polyubiquitination, a signal for proteasomal degradation. Accordingly, compared to WT hZO-2, the half-life of hZO-2 mutants K759R and K992R augmented from 19.9 to 37.3 and 23.3 h, respectively. Instead, the ubiquitination of hZO-2 mutant K730R increased, and its half-life diminished to 6.7 h. The lack of these lysine residues in hZO-2 affects TJ sealing as the peak of TER decreased in monolayers of MDCK cells transfected with any of these mutants. These results highlight the importance of ZO-2 ubiquitination and SUMOylation to maintain a healthy and stable pool of ZO-2 molecules at the TJ.

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Datamining approaches for examining the low prevalence of N‐acetylglutamate synthase deficiency and understanding transcriptional regulation of urea cycle genes

Caldovic,

Ahn,

Andricovic

et al. 2023

J of Inher Metab Disea

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Ammonia, which is toxic to the brain, is converted into non‐toxic urea, through a pathway of six enzymatically catalyzed steps known as the urea cycle. In this pathway, N‐acetylglutamate synthase (NAGS, EC 2.3.1.1) catalyzes the formation of N‐acetylglutamate (NAG) from glutamate and acetyl coenzyme A. NAGS deficiency (NAGSD) is the rarest of the urea cycle disorders, yet is unique in that ureagenesis can be restored with the drug N‐carbamylglutamate (NCG). We investigated whether the rarity of NAGSD could be due to low sequence variation in the NAGS genomic region, high NAGS tolerance for amino acid replacements, and alternative sources of NAG and NCG in the body. We also evaluated whether the small genomic footprint of the NAGS catalytic domain might play a role. The small number of patients diagnosed with NAGSD could result from the absence of specific disease biomarkers and/or short NAGS catalytic domain. We screened for sequence variants in NAGS regulatory regions in patients suspected of having NAGSD and found a novel NAGS regulatory element in the first intron of the NAGS gene. We applied the same datamining approach to identify regulatory elements in the remaining urea cycle genes. In addition to the known promoters and enhancers of each gene, we identified several novel regulatory elements in their upstream regions and first introns. The identification of cis‐regulatory elements of urea cycle genes and their associated transcription factors holds promise for uncovering shared mechanisms governing urea cycle gene expression and potentially lead to new treatments for urea cycle disorders.This article is protected by copyright. All rights reserved.

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ZO-2 favors Hippo signaling, and its re-expression in the steatotic liver by AMPK restores junctional sealing

Cited by 9 publications

References 88 publications

The Role of ZO-2 in Modulating JAM-A and γ-Actin Junctional Recruitment, Apical Membrane and Tight Junction Tension, and Cell Response to Substrate Stiffness and Topography

The Role of ZO-2 in Modulating JAM-A and γ-Actin Junctional Recruitment, Apical Membrane and Tight Junction Tension, and Cell Response to Substrate Stiffness and Topography

Polyubiquitination and SUMOylation Sites Regulate the Stability of ZO-2 Protein and the Sealing of Tight Junctions

Datamining approaches for examining the low prevalence of N‐acetylglutamate synthase deficiency and understanding transcriptional regulation of urea cycle genes

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