含有卵巢肿瘤结构域的蛋白酶 1 (OTUD1) 是一种关键的负调节因子，可促进先天免疫稳态，并广泛参与脓毒症的发病机制。在这项研究中，我们将多组学分析和实验机制研究进行了强有力的整合，以在临床、动物和细胞水平上阐明 OTUD1 在脓毒症中的免疫调节作用。我们的研究揭示了 OTUD1 表达的上调以及通过多组学分析在临床和实验脓毒症中观察到的相关独特变化。重要的是，在体内和体外，OTUD1 被证明可以负向调节炎症反应，并通过机械抑制转化生长因子-β 激活激酶 1 (TAK1) 介导的有丝分裂原的激活，在脓毒症引起的病理性肺损伤中发挥保护作用。 -本研究中的激活蛋白激酶（MAPK）和核因子κ-B（NF-κB）信号通路。随后，我们通过精确定位 OTUD1 可以去泛素化的靶蛋白，探讨了 OTUD1 调节 NF-κB 和 MAPK 通路的分子机制。根据我们实验室先前进行的研究，已经证明肿瘤坏死因子-α诱导蛋白8样2（TIPE2）通过抑制NF-κB和MAPK通路在脓毒性肺损伤和脓毒性脑病中发挥保护作用。因此，我们假设 TIPE2 可能是 OTUD1 的靶蛋白。其他实验，包括 Co-IP、免疫荧光共定位和蛋白质印迹，表明 OTUD1 确实具有去泛素化 TIPE2 的能力。总之，OTUD1 具有作为免疫调节和炎症检查点药物的潜力，并且可以作为脓毒症引起的肺损伤的有前景的治疗靶点。版权所有 © 2024。由 Elsevier Inc. 出版。

Ovarian tumor domain-containing protease 1 (OTUD1) is a critical negative regulator that promotes innate immune homeostasis and is extensively involved in the pathogenesis of sepsis. In this study, we performed a powerful integration of multiomics analysis and an experimental mechanistic investigation to elucidate the immunoregulatory role of OTUD1 in sepsis at the clinical, animal and cellular levels. Our study revealed the upregulation of OTUD1 expression and the related distinctive alterations observed via multiomics profiling in clinical and experimental sepsis. Importantly, in vivo and in vitro, OTUD1 was shown to negatively regulate inflammatory responses and play a protective role in sepsis-induced pathological lung injury by mechanistically inhibiting the activation of the transforming growth factor-beta-activated kinase 1 (TAK1)-mediated mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways in the present study. Subsequently, we probed the molecular mechanisms underlying OTUD1's regulation of NF-κB and MAPK pathways by pinpointing the target proteins that OTUD1 can deubiquitinate. Drawing upon prior research conducted in our laboratory, it has been demonstrated that tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) performs a protective function in septic lung injury and septic encephalopathy by suppressing the NF-κB and MAPK pathways. Hence, we hypothesized that TIPE2 might be a target protein of OTUD1. Additional experiments, including Co-IP, immunofluorescence co-localization, and Western blotting, revealed that OTUD1 indeed has the ability to deubiquitinate TIPE2. In summary, OTUD1 holds potential as an immunoregulatory and inflammatory checkpoint agent, and could serve as a promising therapeutic target for sepsis-induced lung injury.Copyright © 2024. Published by Elsevier Inc.