Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Respiratory and Critical Care Medicine, Suining Central Hospital, Suining, Sichuan, China.
J Cell Mol Med. 2024 Oct;28(19):e70125. doi: 10.1111/jcmm.70125.
Airway mucus hypersecretion, a crucial pathological feature of chronic obstructive pulmonary disease (COPD), contributes to the initiation, progression, and exacerbation of this disease. As a macromolecular mucin, the secretory behaviour of Mucin5AC (MUC5AC) is highly dependent on a series of modifying and folding processes that occur in the endoplasmic reticulum (ER). In this study, we focused on the ER quality control protein KDEL receptor (KDELR) and demonstrated that KDELR2 and MUC5AC were colocalized in the airway epithelium of COPD patients and COPD model rats. In addition, knockdown of KDELR2 markedly reduced the expression of MUC5AC both in vivo and in vitro and knockdown of ATF6 further decreased the levels of KDELR2. Furthermore, pretreatment with 4μ8C, an IRE1α inhibitor, led to a partial reduction in the expression of KDELR2 and MUC5AC both in vivo and in vitro, which indicated the involvement of IRE1α/XBP-1s in the upstream signalling cascade. Our study revealed that KDELR2 plays a crucial role in airway MUC5AC hypersecretion in COPD, which might be dependent on ATF6 and IRE1α/XBP-1s upstream signalling.
气道黏液高分泌是慢性阻塞性肺疾病（COPD）的一个关键病理特征，导致了疾病的发生、进展和恶化。黏蛋白 5AC（MUC5AC）作为一种大分子黏蛋白，其分泌行为高度依赖于内质网（ER）中发生的一系列修饰和折叠过程。在这项研究中，我们专注于 ER 质量控制蛋白 KDEL 受体（KDELR），并证实 KDELR2 和 MUC5AC 在 COPD 患者和 COPD 模型大鼠的气道上皮细胞中存在共定位。此外，KDELR2 的敲低显著减少了体内和体外 MUC5AC 的表达，而 ATF6 的敲低进一步降低了 KDELR2 的水平。此外，IRE1α 抑制剂 4μ8C 的预处理导致体内和体外 KDELR2 和 MUC5AC 的表达部分减少，表明 IRE1α/XBP-1s 参与了上游信号级联反应。我们的研究表明，KDELR2 在 COPD 气道黏液高分泌中起着关键作用，这可能依赖于 ATF6 和 IRE1α/XBP-1s 的上游信号。
