Inhibition of the neddylation E2 enzyme UBE2M in macrophages protects against E. coli-induced sepsis.

Autor:	Wen X; Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China; Department of Oncology, The Affiliated Cangnan Hospital of Wenzhou Medical University, Wenzhou, 325800, Zhejiang, China., Bai S; Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China., Xiong G; Department of Emergency Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, China., Xiu H; Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China., Li J; Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China; Department of Intensive Care, Zhejiang Hospital, No. 1229, Gudun Road, Hangzhou, 310013, Zhejiang, China., Yang J; Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China., Yu Q; Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China., Li B; Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China., Hu R; Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China., Cao L; Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China., Cai Z; Institute of Immunology, and Department of Orthopedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China. Electronic address: caizj@zju.edu.cn., Zhang S; Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China. Electronic address: zhangsf08@zju.edu.cn., Zhang G; Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China; Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education, Hangzhou 310009, Zhejiang, China. Electronic address: genshengzhang@zju.edu.cn.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Dec 13, pp. 108085. Date of Electronic Publication: 2024 Dec 13.
DOI:	10.1016/j.jbc.2024.108085
Abstrakt:	UBE2M, an essential neddylation E2 enzyme, has been implicated in the pathogenesis of various diseases, including cancers, viral infections, and obesity. However, whether UBE2M is involved in the pathogenesis of bacterial sepsis remains unclear. In an Escherichia coli (E. coli)-induced sepsis mouse model, increased UBE2M expression in macrophages in liver and lung tissues postinfection was observed. To further clarify the role of UBE2M in macrophages, mice with macrophage-specific deletion of UBE2M (Lysm + Ube2m f/f ) were constructed. Compared with control mice, these mice presented decreased levels of proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α; reduced sepsis-induced organ damage; and improved survival. Notably, macrophage-specific deletion of UBE2M did not impair E. coli clearance. In vitro experiments also revealed that UBE2M-deficient macrophages produced fewer proinflammatory cytokines after E. coli infection without hindering E. coli clearance. RNA-sequencing analysis revealed that UBE2M deletion in macrophages after LPS stimulation notably suppressed transcriptional activation within the JAK-STAT and Toll-like receptor signaling pathways, which was further confirmed by gene set enrichment analysis. Additionally, Western blotting results confirmed that UBE2M deletion inhibited the activation of the NF-κB, ERK, and JAK-STAT signaling pathways. In conclusion, our findings indicate that specific deletion of UBE2M in macrophages protects against E. coli-induced sepsis by downregulating the excessive inflammatory response, potentially providing a novel strategy against sepsis by targeting UBE2M. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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