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SUMOylation 修饰 Rho 相关蛋白激酶 2 诱导过敏性气道杯状细胞化生。

SUMOylation of Rho-associated protein kinase 2 induces goblet cell metaplasia in allergic airways.

机构信息

Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China.

Key Laboratory of CFDA for Respiratory Drug Research, Zhejiang University School of Medicine, Hangzhou, 310058, China.

出版信息

Nat Commun. 2023 Jul 1;14(1):3887. doi: 10.1038/s41467-023-39600-4.

DOI:10.1038/s41467-023-39600-4
PMID:37393345
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10314948/
Abstract

Allergic asthma is characterized by goblet cell metaplasia and subsequent mucus hypersecretion that contribute to the morbidity and mortality of this disease. Here, we explore the potential role and underlying mechanism of protein SUMOylation-mediated goblet cell metaplasia. The components of SUMOylaion machinery are specifically expressed in healthy human bronchial epithelia and robustly upregulated in bronchial epithelia of patients or mouse models with allergic asthma. Intratracheal suppression of SUMOylation by 2-D08 robustly attenuates not only allergen-induced airway inflammation, goblet cell metaplasia, and hyperreactivity, but IL-13-induced goblet cell metaplasia. Phosphoproteomics and biochemical analyses reveal SUMOylation on K1007 activates ROCK2, a master regulator of goblet cell metaplasia, by facilitating its binding to and activation by RhoA, and an E3 ligase PIAS1 is responsible for SUMOylation on K1007. As a result, knockdown of PIAS1 in bronchial epithelia inactivates ROCK2 to attenuate IL-13-induced goblet cell metaplasia, and bronchial epithelial knock-in of ROCK2(K1007R) consistently inactivates ROCK2 to alleviate not only allergen-induced airway inflammation, goblet cell metaplasia, and hyperreactivity, but IL-13-induced goblet cell metaplasia. Together, SUMOylation-mediated ROCK2 activation is an integral component of Rho/ROCK signaling in regulating the pathological conditions of asthma and thus SUMOylation is an additional target for the therapeutic intervention of this disease.

摘要

变应性哮喘的特征是杯状细胞化生和随后的黏液过度分泌，这导致了这种疾病的发病率和死亡率。在这里，我们探讨了蛋白质 SUMOylation 介导的杯状细胞化生的潜在作用和潜在机制。SUMOylation 机器的组成部分特异性表达于健康的人支气管上皮细胞中，并且在患有变应性哮喘的患者或小鼠模型的支气管上皮细胞中强烈上调。2-D08 通过抑制 SUMOylation 可显著减轻过敏原诱导的气道炎症、杯状细胞化生和高反应性，以及 IL-13 诱导的杯状细胞化生。磷酸蛋白质组学和生化分析表明，SUMOylation 作用于 K1007 可激活 ROCK2，这是杯状细胞化生的主要调节剂，通过促进其与 RhoA 的结合和激活，并且 E3 连接酶 PIAS1 负责 K1007 的 SUMOylation。结果，在支气管上皮细胞中敲低 PIAS1 可使 ROCK2 失活，从而减轻 IL-13 诱导的杯状细胞化生，并且在支气管上皮细胞中敲入 ROCK2(K1007R)可一致地使 ROCK2 失活，从而不仅减轻过敏原诱导的气道炎症、杯状细胞化生和高反应性，还减轻了 IL-13 诱导的杯状细胞化生。总之，SUMOylation 介导的 ROCK2 激活是 Rho/ROCK 信号通路调节哮喘病理状态的一个组成部分，因此 SUMOylation 是该疾病治疗干预的另一个靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bab/10314948/48f17eb3327e/41467_2023_39600_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bab/10314948/c860e0278222/41467_2023_39600_Fig5_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bab/10314948/48f17eb3327e/41467_2023_39600_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bab/10314948/84643191f5cb/41467_2023_39600_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bab/10314948/b9bf19c530a9/41467_2023_39600_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bab/10314948/afbd73c4b6ce/41467_2023_39600_Fig3_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bab/10314948/c860e0278222/41467_2023_39600_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bab/10314948/98224c8f284b/41467_2023_39600_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bab/10314948/48f17eb3327e/41467_2023_39600_Fig7_HTML.jpg

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