USP11 regulates autophagy-dependent ferroptosis after spinal cord ischemia-reperfusion injury by deubiquitinating Beclin 1

Rong, Yuluo; Fan, Jin; Ji, Chengyue; Wang, Zhuanghui; Ge, Xuhui; Wang, Jiaxing; Wu, Ye; Yin, Guoyong; Cai, Wei; Liu, Wei

doi:10.1038/s41418-021-00907-8

Cited by 104 publications

(48 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 6 , 7 Different from primary SCI, which is characterised by destruction of the spinal cord structure, secondary SCI is induced by a series of pathophysiological responses (including hypoxia, ischaemia, oxidative stress, neuroinflammation, cell apoptosis and cell death) following primary injury and is relatively remediable. 8 , 9 , 10 Recently, neuroinflammation has attracted increasing attention for its essential role in secondary SCI. Moreover, extensive evidence indicates that microglial pyroptosis is a significant cause of neuroinflammation after SCI.…”

Section: Introductionmentioning

confidence: 99%

TLR4 aggravates microglial pyroptosis by promoting DDX3X‐mediated NLRP3 inflammasome activation via JAK2/STAT1 pathway after spinal cord injury

Wang

Zhang

et al. 2022

Clinical & Translational Med

View full text Add to dashboard Cite

Background Toll‐like receptor 4 (TLR4) participates in the initiation of neuroinflammation in various neurological diseases, including central nervous system injuries. NLR family pyrin domain containing 3 (NLRP3) inflammasome‐mediated microglial pyroptosis is crucial for the inflammatory response during secondary spinal cord injury (SCI). However, the underlying mechanism by which TLR4 regulates NLRP3 inflammasome activation and microglial pyroptosis after SCI remains uncertain. Methods We established an in vivo mouse model of SCI using TLR4‐knockout (TLR4‐KO) and wild‐type (WT) mice. The levels of pyroptosis, tissue damage and neurological function recovery were evaluated in the three groups (Sham, SCI, SCI‐TLR4‐KO). To identify differentially expressed proteins, tandem mass tag (TMT)‐based proteomics was conducted using spinal cord tissue between TLR4‐KO and WT mice after SCI. For our in vitro model, mouse microglial BV2 cells were exposed to lipopolysaccharides (1 µg/ml, 8 h) and adenosine triphosphate (ATP) (5 mM, 2 h) to induce pyroptosis. A series of molecular biological experiments, including Western blot (WB), real‐time quantitative polymerase chain reaction (RT‐qPCR), enzyme‐linked immunosorbent assay (ELISA), immunofluorescence (IF), immunohistochemical (IHC), chromatin immunoprecipitation (ChIP), Dual‐Luciferase Reporter assay (DLA) and co‐immunoprecipitation (Co‐IP), were performed to explore the specific mechanism of microglial pyroptosis in vivo and in vitro. Results Our results indicated that TLR4 promoted the expression of dead‐box helicase 3 X‐linked (DDX3X), which mediated NLRP3 inflammasome activation and microglial pyroptosis after SCI. Further analysis revealed that TLR4 upregulated the DDX3X/NLRP3 axis by activating the JAK2/STAT1 signalling pathway, and importantly, STAT1 was identified as a transcription factor promoting DDX3X expression. In addition, we found that biglycan was increased after SCI and interacted with TLR4 to jointly regulate microglial pyroptosis through the JAK2/STAT1/DDX3X/NLRP3 axis after SCI. Conclusion Our study preliminarily identified a novel mechanism by which TLR4 regulates NLRP3 inflammasome‐mediated microglial pyroptosis in response to SCI—providing a novel and promising therapeutic target for SCI.

show abstract

Section: Introductionmentioning

confidence: 99%

TLR4 aggravates microglial pyroptosis by promoting DDX3X‐mediated NLRP3 inflammasome activation via JAK2/STAT1 pathway after spinal cord injury

Wang

Zhang

et al. 2022

Clinical & Translational Med

View full text Add to dashboard Cite

show abstract

“…It was reported that, without rescue experiments, the inhibition of USP10 or USP13 expression by three independent siRNA oligos destabilized Beclin-1, whereas overexpressing USP10 or USP13, but not the catalytically inactive mutant, reduced Beclin-1 ubiquitination in vivo (Liu et al, 2011). While this manuscript was under preparation, another group also found evidence that USP11 de-ubiquitinates and stabilizes Beclin-1 to promote autophagy and subsequent autophagy-induced ferroptosis (Rong et al, 2021). These studies, along with previously mentioned reports of autophagy modulation by USP11, failed to provide in vitro evidence of a direct interaction between USP11 and Beclin-1 HeLa cell that reconstituted with HA-tagged vector control, wild type and enzymatic activity defective mutant (C318S) USP11.…”

Section: Discussionmentioning

confidence: 78%

Ubiquitin carboxyl-terminal hydrolase 11 promotes autophagy by de-ubiquitinating and stabilizing Beclin-1

Rao

Song

et al. 2022

GENOME INSTAB. DIS.

View full text Add to dashboard Cite

Autophagy is a major degradation process that degrades and recycles cytoplasmic materials through lysosome for maintaining cellular homeostasis. Dysregulated autophagy is linked with numerous human diseases including cancer. Autophagy marker protein B-cell lymphoma-2 interacting protein 1 (Beclin-1) is essential for autophagosome initiation and maturation. Recently, Ubiquitin carboxyl-terminal hydrolase 11 (USP11) has been reported to promote or inhibit autophagy without identification of any direct target. Here through biochemical reaction in vitro, we demonstrate that USP11 directly interacts with Beclin-1. Both in vitro and in vivo de-ubiquitination assays revealed that USP11 de-ubiquitinates Beclin-1. USP11-mediated de-ubiquitination stabilized Beclin-1 and enhanced the formation of the autophagy-specific class III phosphatidylinositol 3-kinase complexes 1 and 2, thereby promoting autophagy. Together, our results demonstrated that USP11 promotes autophagy under unperturbed conditions by de-ubiquitinating and stabilizing Beclin-1 which may serve as a therapeutic target for autophagy-related diseases.

show abstract

“…By performing the TUNEL assay to assess CC cell apoptosis after hypoxia treatment, we pointed out that hypoxia could induce apoptosis resistance in CC cells (Supplementary Figure 1 ). Ferroptosis is recently found as a form of programmed cell death characterized by iron-dependent lipid peroxide accumulation [ 40 ]. As reported earlier, hypoxia can induce resistance to ferroptosis in pancreatic cancer cells [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Enhances HIF1α Transcription Activity by Upregulating KDM4A and Mediating H3K9me3, Thus Inducing Ferroptosis Resistance in Cervical Cancer Cells

Xiong

Nie

et al. 2022

Stem Cells International

View full text Add to dashboard Cite

Objective. Cervical cancer (CC) is a prevalent cancer in women. Hypoxia plays a critical role in CC cell ferroptosis resistance. This study explored the mechanism of hypoxia in CC cell ferroptosis resistance by regulating HIF1α/KDM4A/H3K9me3. Methods. Cultured SiHa and Hela cells were exposed to CoCl2 and treated with Erastin. Cell viability was detected by MTT assay, and concentrations of iron ion, MDA and GSH were determined using corresponding kits. Expressions of KDM4A, HIF1α, TfR1, DMT1, and H3k9me3 were detected by RT-qPCR, Western blot, and ChIP assay. The correlation of KDM4A and HIF1α was analyzed on Oncomine, UALCAN, and Starbase. CC cells were co-transfected with shKDM4A or/and pcDNA3.1-HIF1α. Iron uptake and release were assessed using the isotopic tracer method. The binding relationship between HIF1α and HRE sequence was verified by dual-luciferase assay. Results. Cell viability and GSH were decreased while iron concentration, MDA, KDM4A, and HIF1α levels were increased in hypoxia conditions. The 2-h hypoxia induced ferroptosis resistance. KDM4A and HIF1α were highly-expressed in CC tissues and positively correlated with each other. KDM4A knockdown attenuated cell resistance to Erastin, increased H3K9me3 level in the HIF1α promoter region, and downregulated HIF1α transcription and translation. H3K9me3 level was increased in the HIF1α promoter after hypoxia. HIF1α overexpression abrogated the function of KDM4A knockdown on ferroptosis in hypoxia conditions. Iron uptake/release and TfR1/DMT1 levels were increased after hypoxia. Hypoxia activated HRE sequence in TfR1 and DMT1 promoters. Conclusion. Hypoxia upregulated KDM4A, enhanced HIF1α transcription, and activated HRE sequence in TfR1 and DMT1 promoters via H3K9me3, thus inducing ferroptosis resistance in CC cells.

show abstract

USP11 regulates autophagy-dependent ferroptosis after spinal cord ischemia-reperfusion injury by deubiquitinating Beclin 1

Cited by 104 publications

References 42 publications

TLR4 aggravates microglial pyroptosis by promoting DDX3X‐mediated NLRP3 inflammasome activation via JAK2/STAT1 pathway after spinal cord injury

TLR4 aggravates microglial pyroptosis by promoting DDX3X‐mediated NLRP3 inflammasome activation via JAK2/STAT1 pathway after spinal cord injury

Ubiquitin carboxyl-terminal hydrolase 11 promotes autophagy by de-ubiquitinating and stabilizing Beclin-1

Hypoxia Enhances HIF1α Transcription Activity by Upregulating KDM4A and Mediating H3K9me3, Thus Inducing Ferroptosis Resistance in Cervical Cancer Cells

Contact Info

Product

Resources

About