Hypoxia-reduced YAP phosphorylation enhances expression of Mucin5AC in nasal epithelial cells of chronic rhinosinusitis with nasal polyps

IF 12 1区医学 Q1 ALLERGY Allergy Pub Date : 2024-11-13 DOI:10.1111/all.16394

Bing Zhong, Jing Liu, Hsiao Hui Ong, Jintao Du, Feng Liu, Yafeng Liu, Luo Ba, Silu Sun, De Yun Wang

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Abstract

Background

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an upper respiratory disease characterized by persistent inflammation of the nasal mucosa. However, the mechanism of abnormal Mucin5AC expression by CRSwNP epithelial cells is not fully understood.

Objective

We investigated the potential role of yes-associated protein (YAP) underlying the mechanism of excessive epithelial Mucin5AC expression in CRSwNP in a hypoxic model.

Methods

Tissue biopsies of CRSwNP (n = 60), chronic rhinosinusitis without nasal polyps (CRSsNP) (n = 9) and healthy controls (n = 30) were investigated together with a well-established hypoxic model of primary human nasal epithelial cells (hNECs). The expression levels of hypoxia inducible factor (HIF)-1α and YAP, and the effect of the signaling axis on mucus secretion in hNECs were analyzed.

Results

We observed a significant elevated expression levels of YAP in patients with CRSwNP and CRSsNP compared to controls. In addition, HIF-1α expression of CRSwNP was higher than that of control group. Under hypoxic conditions, HIF-1α was found to regulate the upregulation of YAP in hNECs. Further investigations revealed that HIF-1α facilitated the activation and nuclear localization of active-YAP by reducing the phosphorylation of YAP. This mechanism appeared to be linked to HIF-1α-mediated inhibition of LATS 1 phosphorylation and subsequent YAP degradation. HIF-1α was shown to promote the expression of P63 and the levels of Mucin5AC in hNECs by enhancing YAP activation.

Conclusion

Our findings indicated that hypoxia enhances YAP activation by decreasing p-LATS 1 and YAP phosphorylation. This has the potential to impact on the proliferation of basal cells and the differentiation of goblet cells in CRSwNP, ultimately leading to a pathological condition characterized by excessive Mucin5AC expression.

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缺氧导致的 YAP 磷酸化降低会增强慢性鼻炎伴鼻息肉鼻腔上皮细胞中 Mucin5AC 的表达

背景慢性鼻炎伴鼻息肉（CRSwNP）是一种上呼吸道疾病，其特点是鼻粘膜持续发炎。然而，CRSwNP 上皮细胞异常表达 Mucin5AC 的机制尚不完全清楚。目的我们在缺氧模型中研究了 yes-associated 蛋白（YAP）在 CRSwNP 上皮 Mucin5AC 过度表达机制中的潜在作用。方法研究了 CRSwNP（n = 60）、无鼻息肉慢性鼻炎（CRSsNP）（n = 9）和健康对照组（n = 30）的组织活检样本，并对原代人鼻上皮细胞（hNECs）的缺氧模型进行了研究。结果我们观察到，与对照组相比，CRSwNP 和 CRSsNP 患者的 YAP 表达水平显著升高。此外，CRSwNP 患者 HIF-1α 的表达高于对照组。研究发现，在缺氧条件下，HIF-1α 可调控 hNECs 中 YAP 的上调。进一步研究发现，HIF-1α通过减少YAP的磷酸化促进了活性YAP的激活和核定位。这一机制似乎与 HIF-1α 介导的 LATS 1 磷酸化抑制及随后的 YAP 降解有关。结论我们的研究结果表明，缺氧通过降低 p-LATS 1 和 YAP 磷酸化增强了 YAP 的活化。这可能会影响 CRSwNP 中基底细胞的增殖和小腺细胞的分化，最终导致以 Mucin5AC 过度表达为特征的病理状态。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Allergy 医学-过敏

CiteScore

26.10

自引率

9.70%

发文量

393

审稿时长

2 months

期刊介绍： Allergy is an international and multidisciplinary journal that aims to advance, impact, and communicate all aspects of the discipline of Allergy/Immunology. It publishes original articles, reviews, position papers, guidelines, editorials, news and commentaries, letters to the editors, and correspondences. The journal accepts articles based on their scientific merit and quality. Allergy seeks to maintain contact between basic and clinical Allergy/Immunology and encourages contributions from contributors and readers from all countries. In addition to its publication, Allergy also provides abstracting and indexing information. Some of the databases that include Allergy abstracts are Abstracts on Hygiene & Communicable Disease, Academic Search Alumni Edition, AgBiotech News & Information, AGRICOLA Database, Biological Abstracts, PubMed Dietary Supplement Subset, and Global Health, among others.