The functions and effects of CUL3-E3 ligases mediated non-degradative ubiquitination

Zhai, Fengguang; Li, Jingyun; Ye, Meng; Jin, Xiaofeng

doi:10.1016/j.gene.2022.146562

Cited by 9 publications

(6 citation statements)

References 217 publications

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“…RING1 has a cross-supported zinc coordination structure, while IBR and RING2 each have two zinc ions that coordinate linearly. Unlike RING E3 ligases, RBR E3 ligases do not directly transfer ubiquitin from E2 ligases to substrate proteins, but form a covalent intermediate with ubiquitin, similar to HECT E3 ligase, then transfers this ubiquitin to the substrate ( 15 , 39 – 43 ). Each RBR E3 ligase has its function.…”

Section: E3 Ligase Familymentioning

confidence: 99%

Regulation of inflammation and immunity in sepsis by E3 ligases

et al. 2023

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Sepsis is a life-threatening organ dysfunction caused by an abnormal infection-induced immune response. Despite significant advances in supportive care, sepsis remains a considerable therapeutic challenge and is the leading cause of death in the intensive care unit (ICU). Sepsis is characterized by initial hyper-inflammation and late immunosuppression. Therefore, immune-modulatory therapies have great potential for novel sepsis therapies. Ubiquitination is an essential post-translational protein modification, which has been known to be intimately involved in innate and adaptive immune responses. Several E3 ubiquitin ligases have been implicated in innate immune signaling and T-cell activation and differentiation. In this article, we review the current literature and discuss the role of E3 ligases in the regulation of immune response and their effects on the course of sepsis to provide insights into the prevention and therapy for sepsis.

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Section: E3 Ligase Familymentioning

confidence: 99%

Regulation of inflammation and immunity in sepsis by E3 ligases

et al. 2023

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“…We examined the linkage speci city of FBXO7-mediated INF2 ubiquitination using commercially available linkage-speci c K48/63-Ub antibodies. K48-linked polyubiquitin chains generally trigger the degradation of substrates via the 26 s proteasome, whereas K63-linked polyubiquitin chains are associated with signal transduction via non-degradative ubiquitination 7 . Corresponding to our previous results, in vivo ubiquitination assays (samples from the same batch as shown in Fig.…”

Section: Identi Cation Of Inf2 As a Degradative Substrate Of Fbxo7mentioning

confidence: 99%

“…The UPS consists of a three-step enzymatic reaction mediated by ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and E3 ubiquitin ligase, culminating in the degradation of the protein with ubiquitin through the proteasome 6 . E3 ubiquitin ligases are the most abundant, especially the CULLIN (CUL) protein family (CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5, CUL7, and CUL9), which speci cally recognizes substrates and plays an important role in cancers 7 . Mutants of E3 ubiquitin ligases are considered key pathogenic factors in cancers 8 .…”

Section: Introductionmentioning

confidence: 99%

FBXO7, a tumor suppressor in endometrial carcinoma, suppresses INF2-associated mitochondrial division

Jin¹,

Zhang

Wang

et al. 2022

Preprint

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Endometrial carcinoma (ECa) is the most common malignant gynecological cancer, with an increased incidence and fatality rate worldwide. Hyperactive INF2-associated mitochondrial division is involved in the occurrence and development of various tumors, including ECa, although the molecular mechanism is unclear. In this study, we confirmed that FBXO7, an E3 ubiquitin ligase, inhibits INF2-associated mitochondrial division through ubiquitination and degradation of INF2 and acts as a tumor suppressor in ECa. Moreover, we found that ECa-associated FBXO7 mutants were defective in the degradation of INF2, promoting ECa cell proliferation and migration through hyperactive INF2-associated mitochondrial division. In addition, our data support the possibility of using the mitochondrial division inhibitor Mdivi-1 in the treatment of FBXO7-mutated ECa. Our study revealed a novel pathogenesis of ECa and may provide a new treatment strategy for ECa patients with FBXO7 mutations.

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“…The UPS consists of a three-step enzymatic reaction mediated by ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and E3 ubiquitin ligase, culminating in the degradation of the protein through the proteasome [ 6 ]. E3 ubiquitin ligases are the most abundant, especially the CULLIN (CUL) protein family (CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5, CUL7, and CUL9), which specifically recognizes substrates and plays an important role in the regulation of protein homeostasis [ 7 ], and E3 ubiquitin ligases mutations are always involved in the occurrence and progression of cancers [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

FBXO7, a tumor suppressor in endometrial carcinoma, suppresses INF2-associated mitochondrial division

et al. 2023

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Endometrial carcinoma (ECa) is the most common malignant gynecological cancer, with an increased incidence and fatality rate worldwide, while the pathogenesis is still largely unknown. In this study, we confirmed that FBXO7, a gene coding FBXO7 E3 ubiquitin ligase, is significantly downregulated and mutated (5.87%; 31/528) in ECa specimens, and the abnormal low expression and mutations of FBXO7 are associated with the occurrence of ECa. We also identify the excessive expression of INF2 protein, a key factor that triggers mitochondrial division by recruiting the DRP1 protein, and the elevated INF2 protein is significantly negatively correlated with the low FBXO7 protein in ECa specimens. Mechanistically, FBXO7 restrains ECa through inhibiting INF2-associated mitochondrial division via FBXO7-mediated ubiquitination and degradation of INF2. Moreover, we found that ECa-associated FBXO7 mutants are defective in the ubiquitination and degradation of INF2, promoting ECa cells proliferation, migration and apoptosis inhibition via inducing mitochondrial hyper-division. In addition, we found that it could reverse FBXO7 deletion or ECa-associated FBXO7 mutants-induced proliferation, migration, apoptosis inhibition and mitochondrial hyper-division of ECa cells by INF2 or DNM1L knockdown, or DRP1 inhibitor Mdivi-1. In summary, our study shows that FBXO7 acts as a novel tumor suppressor in ECa by inhibiting INF2-DRP1 axis-associated mitochondrial division through the ubiquitination and degradation of INF2 while the effect is destroyed by ECa-associated FBXO7 and INF2 mutants, highlights the key role of FBXO7-INF2-DRP1 axis in ECa tumorigenesis and provides a new viewpoint to treat ECa patients with FBXO7 deletion or mutations by targeting INF2-DRP1 axis-associated mitochondrial division.

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The functions and effects of CUL3-E3 ligases mediated non-degradative ubiquitination

Cited by 9 publications

References 217 publications

Regulation of inflammation and immunity in sepsis by E3 ligases

Regulation of inflammation and immunity in sepsis by E3 ligases

FBXO7, a tumor suppressor in endometrial carcinoma, suppresses INF2-associated mitochondrial division

FBXO7, a tumor suppressor in endometrial carcinoma, suppresses INF2-associated mitochondrial division

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