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

Dan Tan, Meiping Lu (), Yuqing Cai, Weibo Qi, Fugen Wu, Hangyang Bao, Meiyu Qv, Qiangqiang He, Yana Xu, Xiangzhi Wang, Tingyu Shen, Jiahao Luo, Yangxun He, Junsong Wu, Lanfang Tang, Muhammad Qasim Barkat, Chengyun Xu () and Ximei Wu ()
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Dan Tan: Zhejiang University School of Medicine
Meiping Lu: the Children’s Hospital of Zhejiang University School of Medicine
Yuqing Cai: the Children’s Hospital of Zhejiang University School of Medicine
Weibo Qi: the Affiliated Hospital of Jiaxing University
Fugen Wu: the First People’s Hospital of Wenling City
Hangyang Bao: Zhejiang University School of Medicine
Meiyu Qv: Zhejiang University School of Medicine
Qiangqiang He: Zhejiang University School of Medicine
Yana Xu: Zhejiang University School of Medicine
Xiangzhi Wang: the Children’s Hospital of Zhejiang University School of Medicine
Tingyu Shen: Zhejiang University School of Medicine
Jiahao Luo: Zhejiang University School of Medicine
Yangxun He: Zhejiang University School of Medicine
Junsong Wu: Zhejiang University School of Medicine
Lanfang Tang: the Children’s Hospital of Zhejiang University School of Medicine
Muhammad Qasim Barkat: Zhejiang University School of Medicine
Chengyun Xu: Zhejiang University School of Medicine
Ximei Wu: Zhejiang University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39600-4

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