The Hippo–YAP pathway regulates the proliferation of alveolar epithelial progenitors after acute lung injury

Hu, Chen; Sun, Jianhui; Du, Juan; Wen, Dalin; Lu, Hongxiang; Zhang, Huacai; Yang, Xue; Zhang, Anqiang; Yang, Chen; Jiang, Jianxin

doi:10.1002/cbin.11098

Cited by 29 publications

(26 citation statements)

References 28 publications

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“…YAP, the primary transcriptional effector of the Hippo pathway, is distributed in respiratory epithelial cells 40 . With roles in lung homeostasis and development 41 , YAP was increased after murine lung injury due to hemorrhage and LPS 42 , and recently associated with alveolar epithelium repair and regeneration following pneumonectomy 43 or bacterial pneumonia 44 . It also contributes to barrier function by regulating and responding to actin cytoskeleton dynamics 29 .…”

Section: Discussionmentioning

confidence: 99%

Lung Atelectasis Promotes Immune and Barrier Dysfunction as Revealed by Transcriptome Sequencing in Female Sheep

Zeng¹,

Ribeiro²,

Hinoshita³

et al. 2020

Anesthesiology

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Background Pulmonary atelectasis is frequent in clinical settings. Yet there is limited mechanistic understanding and substantial clinical and biologic controversy on its consequences. The authors hypothesize that atelectasis produces local transcriptomic changes related to immunity and alveolar–capillary barrier function conducive to lung injury and further exacerbated by systemic inflammation. Methods Female sheep underwent unilateral lung atelectasis using a left bronchial blocker and thoracotomy while the right lung was ventilated, with (n = 6) or without (n = 6) systemic lipopolysaccharide infusion. Computed tomography guided samples were harvested for NextGen RNA sequencing from atelectatic and aerated lung regions. The Wald test was used to detect differential gene expression as an absolute fold change greater than 1.5 and adjusted P value (Benjamini–Hochberg) less than 0.05. Functional analysis was performed by gene set enrichment analysis. Results Lipopolysaccharide-unexposed atelectatic versus aerated regions presented 2,363 differentially expressed genes. Lipopolysaccharide exposure induced 3,767 differentially expressed genes in atelectatic lungs but only 1,197 genes in aerated lungs relative to the corresponding lipopolysaccharide-unexposed tissues. Gene set enrichment for immune response in atelectasis versus aerated tissues yielded negative normalized enrichment scores without lipopolysaccharide (less than –1.23, adjusted P value less than 0.05) but positive scores with lipopolysaccharide (greater than 1.33, adjusted P value less than 0.05). Leukocyte-related processes (e.g., leukocyte migration, activation, and mediated immunity) were enhanced in lipopolysaccharide-exposed atelectasis partly through interferon-stimulated genes. Furthermore, atelectasis was associated with negatively enriched gene sets involving alveolar–capillary barrier function irrespective of lipopolysaccharide (normalized enrichment scores less than –1.35, adjusted P value less than 0.05). Yes-associated protein signaling was dysregulated with lower nuclear distribution in atelectatic versus aerated lung (lipopolysaccharide-unexposed: 10.0 ± 4.2 versus 13.4 ± 4.2 arbitrary units, lipopolysaccharide-exposed: 8.1 ± 2.0 versus 11.3 ± 2.4 arbitrary units, effect of lung aeration, P = 0.003). Conclusions Atelectasis dysregulates the local pulmonary transcriptome with negatively enriched immune response and alveolar–capillary barrier function. Systemic lipopolysaccharide converts the transcriptomic immune response into positive enrichment but does not affect local barrier function transcriptomics. Interferon-stimulated genes and Yes-associated protein might be novel candidate targets for atelectasis-associated injury. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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Section: Discussionmentioning

confidence: 99%

Lung Atelectasis Promotes Immune and Barrier Dysfunction as Revealed by Transcriptome Sequencing in Female Sheep

Zeng¹,

Ribeiro²,

Hinoshita³

et al. 2020

Anesthesiology

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“…Activated YAP is central to the maintenance of alveolar epithelial cell populations and their transcriptional programs (25). YAP is a critical regulator of AT2 cell proliferation after injury (26), and loss of YAP during recovery after infection can delay regenerative responses of AT2 cells (27). Recently, endosomal targeting of ATP8A1 and cytosolic exposure of PtdSer on endosome membranes were shown to activate YAP in selected cell lines (23).…”

Section: Significancementioning

confidence: 99%

AP-3–dependent targeting of flippase ATP8A1 to lamellar bodies suppresses activation of YAP in alveolar epithelial type 2 cells

Kook

Wang

Meng

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Lamellar bodies (LBs) are lysosome-related organelles (LROs) of surfactant-producing alveolar type 2 (AT2) cells of the distal lung epithelium. Trafficking pathways to LBs have been understudied but are likely critical to AT2 cell homeostasis given associations between genetic defects of endosome to LRO trafficking and pulmonary fibrosis in Hermansky Pudlak syndrome (HPS). Our prior studies uncovered a role for AP-3, defective in HPS type 2, in trafficking Peroxiredoxin-6 to LBs. We now show that the P4-type ATPase ATP8A1 is sorted by AP-3 from early endosomes to LBs through recognition of a C-terminal dileucine-based signal. Disruption of the AP-3/ATP8A1 interaction causes ATP8A1 accumulation in early sorting and/or recycling endosomes, enhancing phosphatidylserine exposure on the cytosolic leaflet. This in turn promotes activation of Yes-activating protein, a transcriptional coactivator, augmenting cell migration and AT2 cell numbers. Together, these studies illuminate a mechanism whereby loss of AP-3–mediated trafficking contributes to a toxic gain-of-function that results in enhanced and sustained activation of a repair pathway associated with pulmonary fibrosis.

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“…The Hippo pathway, first discovered in Drosophila melanogaster , is highly conserved across species 1. This pathway regulates not only organ size but also cell proliferation, differentiation, and apoptosis 2,3. In recent years, increasing attention has been focused on the relationship between the Hippo pathway and the proliferation, invasion, and metastasis of tumor cells 4.…”

Section: Introductionmentioning

confidence: 99%

<p>FRMPD1 activates the Hippo pathway via interaction with WWC3 to suppress the proliferation and invasiveness of lung cancer cells</p>

Rong

Han

Lin

et al. 2019

CMAR

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Purpose: The expression of FERM-domain-containing protein-1 (FRMPD1)/FERM and PDZ domain-containing protein-2 (FRMD2) in malignant tumors, including lung cancer, and its underlying molecular mechanism have not been reported yet. Materials and methods: Immunohistochemistry was performed to analyze the expression of FRMPD1 in lung cancer tissues, and statistical analysis was applied to analyze the relationship between FRMPD1 expression and clinicopathological factors. The biological effects of FRMPD1 on lung cancer cell proliferation and invasion were determined by functional experiments both in vivo and in vitro. Immunoblotting, RT-qPCR, dual-luciferase assay, and immunofluorescence were performed to demonstrate whether FRMPD1 stimulates Hippo signaling. Co-immunoprecipitation assays were used to clarify the underlying role of FRMPD1 in Hippo pathway activation via interaction with WW and C2 domain containing protein-3 (WWC3). Results: We found that FRMPD1 expression in lung cancer specimens was lower than that in normal bronchial epithelium and normal submucosal glands. FRMPD1 expression had a negative correlation with age, Tumor-Node-Metastasis (TNM) stage, lymph node metastasis, as well as poor prognosis. Moreover, ectopic expression of FRMPD1 significantly inhibited the proliferation and invasion of lung cancer cells, and inhibition of FRMPD1 expression led to opposite effects. Mechanistically, we found that FRMPD1 interacted with the C-terminal PDZ binding motif of WWC3 via its PSD95/DLG/ZO1 (PDZ) domain and promoted the phosphorylation of large tumor suppressor-1 (LATS1), thus inhibiting the nuclear translocation of yes-associated protein (YAP). Conclusion: FRMPD1 could activate the Hippo pathway and ultimately inhibit the malignant behavior of lung cancer cells through its interaction with WWC3. This work will provide an important experimental basis for the discovery of novel biomarkers of lung cancer and the development of targeted drugs.

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The Hippo–YAP pathway regulates the proliferation of alveolar epithelial progenitors after acute lung injury

Cited by 29 publications

References 28 publications

Lung Atelectasis Promotes Immune and Barrier Dysfunction as Revealed by Transcriptome Sequencing in Female Sheep

Lung Atelectasis Promotes Immune and Barrier Dysfunction as Revealed by Transcriptome Sequencing in Female Sheep

AP-3–dependent targeting of flippase ATP8A1 to lamellar bodies suppresses activation of YAP in alveolar epithelial type 2 cells

<p>FRMPD1 activates the Hippo pathway via interaction with WWC3 to suppress the proliferation and invasiveness of lung cancer cells</p>

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