Structures, functions, and inhibitors of LUBAC and its related diseases

Ning, Shuo; Luo, Lingling; Yu, Beiming; Mai, Dina; Wang, Feng

doi:10.1002/jlb.3mr0222-508r

Cited by 5 publications

(4 citation statements)

References 107 publications

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“…Recently, the role of M1-Ub modifications generated by the LUBAC complex has been representing a more important function in the regulation of the NF-κB pathway [ 37 , 38 ]. It has been reported that the inhibition of LUBAC complex dysfunction could be considered an effective treatment for tumours [ 39 ]. Ruiz et al.…”

Section: Discussionmentioning

confidence: 99%

Peptidase inhibitor (PI16) impairs bladder cancer metastasis by inhibiting NF-κB activation via disrupting multiple-site ubiquitination of NEMO

Kuang,

Zhang,

et al. 2023

Cell Mol Biol Lett

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Background Bladder cancer (BLCA) is a malignancy that frequently metastasizes and leads to poor patient prognosis. It is essential to understand the molecular mechanisms underlying the progression and metastasis of BLCA and identify potential biomarkers. Methods The expression of peptidase inhibitor 16 (PI16) was analysed using quantitative PCR, immunoblotting and immunohistochemistry assays. The functional roles of PI16 were evaluated using wound healing, transwell, and human umbilical vein endothelial cell tube formation assays, as well as in vivo tumour models. The effects of PI16 on nuclear factor κB (NF-κB) signalling activation were examined using luciferase reporter gene systems, immunoblotting and immunofluorescence assays. Co-immunoprecipitation was used to investigate the interaction of PI16 with annexin-A1 (ANXA1) and NEMO. Results PI16 expression was downregulated in bladder cancer tissues, and lower PI16 levels correlated with disease progression and poor survival in patients with BLCA. Overexpressing PI16 inhibited BLCA cell growth, motility, invasion and angiogenesis in vitro and in vivo, while silencing PI16 had the opposite effects. Mechanistically, PI16 inhibited the activation of the NF-κB pathway by interacting with ANXA1, which inhibited K63 and M1 ubiquitination of NEMO. Conclusions These results indicate that PI16 functions as a tumour suppressor in BLCA by inhibiting tumour growth and metastasis. Additionally, PI16 may serve as a potential biomarker for metastatic BLCA.

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Section: Discussionmentioning

confidence: 99%

Peptidase inhibitor (PI16) impairs bladder cancer metastasis by inhibiting NF-κB activation via disrupting multiple-site ubiquitination of NEMO

Kuang,

Zhang,

et al. 2023

Cell Mol Biol Lett

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“…The best-known RBR member is Parkin whose ligase activity is associated with neurodegeneration ( Pickrell and Youle 2015 ). Two RBR E3s (HOIL-1L and HOIP) and an adaptor SHARPIN form an E3 enzyme complex, the liner Ub chain assembly complex (LUBAC), which generates linear polyUb chains and regulates apoptosis, inflammation, angiogenesis, and immune diseases ( Fu et al 2021 ; Ning et al 2022 ). The remaining 11 RBRs are Ariadne E3s (ARIH1, ARIH2, CUL9, and ANKIB1), RNF14, RNF144A, RNF144B, RNF19A, RNF18B, RNF216, and RNF217.…”

Section: The Ubiquitination Systemmentioning

confidence: 99%

The ubiquitin codes in cellular stress responses

et al. 2023

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Ubiquitination/ubiquitylation, one of the most fundamental post-translational modifications (PTMs), regulates almost every critical cellular process in eukaryotes. Emerging evidence has shown that essential components of numerous biological processes undergo ubiquitination in mammalian cells upon exposure to diverse stresses, from exogenous factors to cellular reactions, causing a dazzling variety of functional consequences. Various forms of ubiquitin signals generated by ubiquitylation events in specific milieus, known as ubiquitin codes, constitute an intrinsic part of myriad cellular stress responses. These ubiquitination events, leading to proteolytic turnover of the substrates or just switch in functionality, initiate, regulate or supervise multiple cellular stress-associated responses, supporting adaptation, homeostasis recovery, and survival of the stressed cells. In this review, we attempted to summarize the crucial roles of ubiquitination in response to different environmental and intracellular stresses, while discussing how stresses modulate the ubiquitin system. This review also updates the most recent advances in understanding ubiquitination machinery as well as different stress responses, and discusses some important questions that may warrant future investigation.

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“…The linear ubiquitin chain assembly complex (LUBAC) has three subunits, including ring finger protein 31 (RNF31/HOIP), RanBP-type and C3HC4-type zinc finger containing 1 (RBCK1/ HOIL-1), and SHANK-associated RH domain interacting protein (SHARPIN/SIPL1) [35,36]. LUBAC regulates downstream signaling pathways of TCR, BCR, TNFR1, TLR, and NLRP3 [37][38][39][40][41]. All three LUBAC components play roles in thymic Treg development, and deletion of RNF31 results in massive loss of peripheral Tregs [42].…”

Section: Rnf31mentioning

confidence: 99%

Ubiquitin-Dependent Regulation of Treg Function and Plasticity

2022

Journal of Cellular Immunology

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Immunosuppressive regulatory T cells (Tregs) are critical in maintaining immune tolerance and homeostasis of the immune system. Treg dysfunction leads to autoimmunity, while active Tregs in the tumor microenvironment hinders anti-tumor immune responses. As a master transcription factor of Tregs, forkhead box P3 (Foxp3) coordinates with different proteins in regulating Treg development and function. Such events are controlled by a series of post-translational modifications (PTMs). Among them, ubiquitin-dependent modifications of Foxp3 regulate degradation, nuclear localization, signal transduction, and suppressive function of the protein. Research has discovered different partners involved in the ubiquitination and deubiquitination of Foxp3. Understanding the mechanisms of these key PTMs of Foxp3 shall expand our knowledge of Tregs and pave the way for targeting Tregs in treating autoimmune diseases and cancer.

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Structures, functions, and inhibitors of LUBAC and its related diseases

Cited by 5 publications

References 107 publications

Peptidase inhibitor (PI16) impairs bladder cancer metastasis by inhibiting NF-κB activation via disrupting multiple-site ubiquitination of NEMO

Peptidase inhibitor (PI16) impairs bladder cancer metastasis by inhibiting NF-κB activation via disrupting multiple-site ubiquitination of NEMO

The ubiquitin codes in cellular stress responses

Ubiquitin-Dependent Regulation of Treg Function and Plasticity

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