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

by Selleckchem | Nov 07 2023

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.

Comments:

The passage you provided describes a study exploring the potential role and mechanism of protein SUMOylation in goblet cell metaplasia, a characteristic feature of allergic asthma. The researchers found that the components of the SUMOylation machinery are specifically expressed in healthy human bronchial epithelia (the cells lining the airways) and are upregulated in the bronchial epithelia of patients or mouse models with allergic asthma.

To investigate the effects of SUMOylation on goblet cell metaplasia, the researchers used a method called intratracheal suppression of SUMOylation using a compound called 2-D08. They found that inhibiting SUMOylation robustly attenuated allergen-induced airway inflammation, goblet cell metaplasia, and hyperreactivity. Furthermore, they discovered that SUMOylation was also involved in IL-13-induced goblet cell metaplasia, which is a process mediated by a specific immune signaling molecule called IL-13.

Phosphoproteomics and biochemical analyses were performed to understand the molecular mechanisms underlying SUMOylation-mediated goblet cell metaplasia. The researchers identified a specific site, K1007, on a protein called ROCK2 that is activated by SUMOylation. ROCK2 is a master regulator of goblet cell metaplasia and is part of a signaling pathway involving another protein called RhoA. SUMOylation on K1007 was found to facilitate the binding of ROCK2 to RhoA and its subsequent activation. The researchers also identified an E3 ligase called PIAS1 as the enzyme responsible for the SUMOylation of K1007.

To further validate the role of SUMOylation and ROCK2 in goblet cell metaplasia, the researchers performed additional experiments. Knockdown of PIAS1 in bronchial epithelial cells resulted in the inactivation of ROCK2 and attenuated IL-13-induced goblet cell metaplasia. Additionally, they introduced a mutation in the bronchial epithelial cells to create a knock-in of a non-SUMOylatable form of ROCK2 (ROCK2(K1007R)). This knock-in prevented the activation of ROCK2 and alleviated not only allergen-induced airway inflammation, goblet cell metaplasia, and hyperreactivity but also IL-13-induced goblet cell metaplasia.

In summary, the study demonstrates that SUMOylation-mediated activation of ROCK2 plays a crucial role in the Rho/ROCK signaling pathway involved in the development of goblet cell metaplasia in asthma. It suggests that targeting SUMOylation could be a potential therapeutic strategy for treating allergic asthma by mitigating the pathological features of the disease.