The SCFFBXO3 ubiquitin E3 ligase regulates inflammation in atherosclerosis

Chandra, Divay; Londino, J.D.; Alexander, Shaun; Bednash, Joseph S.; Zhang, Yingze; Friedlander, Robert M.; Daskivich, Grant J.; Carlisle, Diane L.; Lariviere, William R.; Nakassa, Ana Carolina Igami; Ross, Mark A.; Croix, Claudette St.; Nyunoya, Toru; Sciurba, Frank C.; Chen, Bill; Mallampalli, Rama K.

doi:10.1016/j.yjmcc.2018.11.006

Cited by 8 publications

(10 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, our results demonstrated that FBXO3 protein expression was increased after I/R injury, and specifically expressed in neurons; furthermore, in an SD rat MCAO/R model, si-FBXO3 could partially recover the infarct volumes and lower the neurological deficit scores, while in HT22 cells, si-FBXO3 transfection elevated the neuronal survival rate and attenuated the neuronal apoptosis caused by OGD/R. Moreover, FBXO3 is known to stimulate cytokine secretion by destabilizing FBXL2 through UPS [ 14 ], and exert its pro-inflammatory effect in a variety of disease models including lung I/R injury [ 20 ], pneumonia, sepsis [ 14 ], and atherosclerosis [ 19 ]. In concert with these findings, our results revealed that si-FBXO3 decreased the expression of IL-1β, IL-18, and TNF-α, verifying that FBXO3 is a pro-inflammatory regulator in I/R injury both in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Beyond the connection with CNS, FBXO3 has been demonstrated to mediate ubiquitination degradation of F-Box and Leucine Rich Repeat Protein 2 (FBXL2) [ 14 ], thereby promoting inflammatory cytokines’ expression [ 15 ] and rescuing the expression of NLR Family Pyrin Domain Containing 3 (NLRP3) [ 16 ], which has been confirmed to prompt inflammatory cascade and neuronal damage in ischemic stroke [ 17 , 18 ]. Aside from the connection between FBXO3 and inflammation mentioned above, FBXO3 has been reported to promote inflammation in several kinds of diseases, including pneumonia, sepsis [ 14 ], and atherosclerosis [ 19 ]. In addition, FBXO3 inhibitor BC-1215 attenuates ischemia–reperfusion-induced lung injury in rat models [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

E3 Ubiquitin Ligase FBXO3 Drives Neuroinflammation to Aggravate Cerebral Ischemia/Reperfusion Injury

Gao

Xiao²,

Wang³

et al. 2022

IJMS

View full text Add to dashboard Cite

Ischemic stroke, one of the most universal causes of human mortality and morbidity, is pathologically characterized by inflammatory cascade, especially during the progression of ischemia/reperfusion (I/R) injury. F-Box Protein 3 (FBXO3), a substrate-recognition subunit of SKP1-cullin 1-F-box protein (SCF) E3 ligase complexes, has recently been proven to be severed as an underlying pro-inflammatory factor in pathological processes of diverse diseases. Given these considerations, the current study aims at investigating whether FBXO3 exerts impacts on inflammation in cerebral I/R injury. In this study, first, it was verified that FBXO3 protein expression increased after a middle cerebral artery occlusion/reperfusion (MCAO/R) model in Sprague–Dawley (SD) rats and was specifically expressed in neurons other than microglia or astrocytes. Meanwhile, in mouse hippocampal neuronal cell line HT22 cells, the elevation of FBXO3 protein was observed after oxygen and glucose deprivation/reoxygenation (OGD/R) treatment. It was also found that interference of FBXO3 with siRNA significantly alleviated neuronal damage via inhibiting the inflammatory response in I/R injury both in vivo and in vitro. The FBXO3 inhibitor BC-1215 was used to confirm the pro-inflammatory effect of FBXO3 in the OGD/R model as well. Furthermore, by administration of FBXO3 siRNA and BC-1215, FBXO3 was verified to reduce the protein level of Homeodomain-Interacting Protein Kinase 2 (HIPK2), likely through the ubiquitin–proteasome system (UPS), to aggravate cerebral I/R injury. Collectively, our results underline the detrimental effect FBXO3 has on cerebral I/R injury by accelerating inflammatory response, possibly through ubiquitylating and degrading HIPK2. Despite the specific interaction between FBXO3 and HIPK2 requiring further study, we believe that our data suggest the therapeutic relevance of FBXO3 to ischemic stroke and provide a new perspective on the mechanism of I/R injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

E3 Ubiquitin Ligase FBXO3 Drives Neuroinflammation to Aggravate Cerebral Ischemia/Reperfusion Injury

Gao

Xiao²,

Wang³

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…FBXO3 has been found to stimulate cytokine secretion via controlling the degradation of Fbxl2 and subsequent upregulation of TNFR-associated factor (TRAF) proteins (90). FBXO3 was also reported to potentiated vascular inflammation and atherosclerosis (91). One study used rat fibroblast-like synoviocytes (FLSs) to construct knee osteoarthritis cell model.…”

Section: Fbxo3mentioning

confidence: 99%

Elucidating the role of ubiquitination and deubiquitination in osteoarthritis progression

Zheng

Chen

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

Osteoarthritis is non-inflammatory degenerative joint arthritis, which exacerbates disability in elder persons. The molecular mechanisms of osteoarthritis are elusive. Ubiquitination, one type of post-translational modifications, has been demonstrated to accelerate or ameliorate the development and progression of osteoarthritis via targeting specific proteins for ubiquitination and determining protein stability and localization. Ubiquitination process can be reversed by a class of deubiquitinases via deubiquitination. In this review, we summarize the current knowledge regarding the multifaceted role of E3 ubiquitin ligases in the pathogenesis of osteoarthritis. We also describe the molecular insight of deubiquitinases into osteoarthritis processes. Moreover, we highlight the multiple compounds that target E3 ubiquitin ligases or deubiquitinases to influence osteoarthritis progression. We discuss the challenge and future perspectives via modulation of E3 ubiquitin ligases and deubiquitinases expression for enhancement of the therapeutic efficacy in osteoarthritis patients. We conclude that modulating ubiquitination and deubiquitination could alleviate the osteoarthritis pathogenesis to achieve the better treatment outcomes in osteoarthritis patients.

show abstract

“…FBXO3 also potentiates vascular inflammation and increases atherosclerosis. Depletion of FBXO3 protein in macrophages eliminates oxidatively modified low-density lipoprotein-induced inflammation without affecting oxidized low-density lipoprotein uptake by macrophages ( Chandra et al, 2019 ). Treatment with BC-1215 reduces the release of IL-1β and TNF-α ( Chandra et al, 2019 ), which alleviates FBXO3-induced vascular inflammation and atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

“…Depletion of FBXO3 protein in macrophages eliminates oxidatively modified low-density lipoprotein-induced inflammation without affecting oxidized low-density lipoprotein uptake by macrophages ( Chandra et al, 2019 ). Treatment with BC-1215 reduces the release of IL-1β and TNF-α ( Chandra et al, 2019 ), which alleviates FBXO3-induced vascular inflammation and atherosclerosis. These data suggest that FBXO3 is a novel target of drug design that aims to alleviate atherosclerosis driven by pro-inflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

Diverse Roles of F-BoxProtein3 in Regulation of Various Cellular Functions

Zhang

Bao

Gao

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Accumulated evidence shows that the F-box protein 3 (FBXO3) has multiple biological functions, including regulation of immune pathologies, neuropathic diseases and antiviral response. In this review article, we focus on the role of FBXO3 in inflammatory disorders and human malignancies. We also describe the substrates of FBXO3, which contribute to inflammatory disorders and cancers. We highlight that the high expression of FBXO3 is frequently observed in rheumatoid arthritis, leukemia, pituitary adenoma, and oral squamous cell carcinoma. Moreover, we discuss the regulation of FBXO3 by both carcinogens and cancer preventive agents. Our review provides a comprehensive understanding of the role of FBXO3 in various biological systems and elucidates how FBXO3 regulates substrate ubiquitination and degradation during various physiological and pathological processes. Therefore, FBXO3 can be a novel target in the treatment of human diseases including carcinomas.

show abstract

The SCFFBXO3 ubiquitin E3 ligase regulates inflammation in atherosclerosis

Cited by 8 publications

References 43 publications

E3 Ubiquitin Ligase FBXO3 Drives Neuroinflammation to Aggravate Cerebral Ischemia/Reperfusion Injury

E3 Ubiquitin Ligase FBXO3 Drives Neuroinflammation to Aggravate Cerebral Ischemia/Reperfusion Injury

Elucidating the role of ubiquitination and deubiquitination in osteoarthritis progression

Diverse Roles of F-BoxProtein3 in Regulation of Various Cellular Functions

Contact Info

Product

Resources

About