期刊
FEBS JOURNAL
卷 289, 期 17, 页码 5180-5197出版社
WILEY
DOI: 10.1111/febs.16425
关键词
cell stress; hypoxia; linear ubiquitin chain; NF-kappa B; sterile inflammation
资金
- MiniHypoxy platform
- Pascal Meier, Francois Leulier, Bloomington Drosophila Stock Center [NIH P40OD018537]
- Academy of Finland [321850]
- Sigrid Juselius Foundation
- Abo Akademi University Foundation
- Victoriastiftelsen
- Svenska Kulturfonden
- Orion Research Foundation sr
- Turku Doctoral Network in Molecular Biosciences
- Center of Excellence in Cellular Mechanostasis at Abo Akademi University
- InFLAMES Flagship Programme of the Academy of Finland [337531]
- Academy of Finland (AKA) [321850, 337531, 321850] Funding Source: Academy of Finland (AKA)
M1-Ub chains play a critical role in the NF-κB signaling pathway during inflammatory response induced by stress conditions in both flies and mammals. The linear ubiquitin E3 ligase LUBEL in flies catalyzes the formation of M1-Ub chains and protects flies from stress-induced death by activating the NF-κB signaling pathway.
Methionine 1 (M1)-linked ubiquitination plays a key role in the regulation of inflammatory nuclear factor-kappa B (NF-kappa B) signalling and is important for clearance of pathogen infection in Drosophila melanogaster. M1-linked ubiquitin (M1-Ub) chains are assembled by the linear ubiquitin E3 ligase (LUBEL) in flies. Here, we have studied the role of LUBEL in sterile inflammation induced by different types of cellular stresses. We have found that the LUBEL catalyses formation of M1-Ub chains in response to hypoxic, oxidative and mechanical stress conditions. LUBEL is shown to be important for flies to survive low oxygen conditions and paraquat-induced oxidative stress. This protective action seems to be driven by stress-induced activation of the NF-kappa B transcription factor Relish via the immune deficiency (Imd) pathway. In addition to LUBEL, the intracellular mediators of Relish activation, including the transforming growth factor activating kinase 1 (Tak1), Drosophila inhibitor of apoptosis (IAP) Diap2, the I kappa B kinase gamma (IKK gamma) Kenny and the initiator caspase Death-related ced-3/Nedd2-like protein (Dredd), but not the membrane receptor peptidoglycan recognition protein (PGRP)-LC, are shown to be required for sterile inflammatory response and survival. Finally, we showed that the stress-induced upregulation of M1-Ub chains in response to hypoxia, oxidative and mechanical stress is also induced in mammalian cells and protects from stress-induced cell death. Taken together, our results suggest that M1-Ub chains are important for NF-kappa B signalling in inflammation induced by stress conditions often observed in chronic inflammatory diseases and cancer.
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