Modulation of Immune Cell Functions by the E3 Ligase Cbl-b

Lutz-Nicoladoni, Christina; Wolf, Dominik; Sopper, Sieghart

doi:10.3389/fonc.2015.00058

Cited by 71 publications

(77 citation statements)

References 164 publications

(243 reference statements)

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“…In addition to USP15, for instance, accumulating evidence suggests that Cbl-b also regulates innate immunity responses and is important in host defense to pathogens [142]. Understanding the signaling pathways in innate and adaptive immune cells is, therefore, essential for efficient manipulation of Cbl-b in emerging immunotherapies for human disorders such as autoimmune diseases, infections and cancer [143,144]. At the same time, such E3 ligases can be targeted with small molecules as showcased in our USP15 project.…”

Section: Future Perspectivementioning

confidence: 99%

Targeting Ubiquitination for Cancer Therapies

Morrow¹,

Lin

Sun

et al. 2015

Future Med. Chem.

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Ubiquitination, the structured degradation and turnover of cellular proteins, is regulated by the ubiquitin-proteasome system. Most proteins that are critical for cellular regulations and functions are targets of the process. Ubiquitination is comprised of a sequence of three enzymatic steps, and aberrations in the pathway can lead to tumor development and progression as observed in many cancer types. Recent evidence indicates that targeting the ubiquitin-proteasome system is effective for certain cancer treatment, but many more potential targets might have been previously overlooked. In this review, we will discuss the current state of small molecules that target various elements of ubiquitination. Special attention will be given to novel inhibitors of E3 ubiquitin ligases, especially those in the SCF family.Ubiquitination, a step in the nonlysosomal degradation of proteins, is a crucial post-translational modification in eukaryotic organisms. Rapid and timely degradation of transcriptional regulators and other proteins by the ubiquitin-proteasome system (UPS) regulates a wide variety of cellular processes [1]. Ubiquitination involves covalent attachment of ubiquitin, a small 8-kDa protein, to a substrate and results in recognition and shuttling of the substrate to the 26S proteasome complex for degradation [2]. It is important to note that the ubiquitination process combined with the proteasome complex step is also referred to as the ubiquitin-proteasome system (UPS) or ubiquitin proteasome pathway (UPP).The ubiquitination process is tightly controlled by three families of enzymes: ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and finally ubiquitin-protein enzymes (E3s). There exists two E1 enzymes with ubiquitin-activating capability: UBA1 being the primary E1 and the recently discovered UBA6 with unclear functions and uncharacterized regulations [3,4]. In contrast to the small number of E1s, there are approximately 40 E2s [5,6] and 500-1000 human E3 ligases, providing both specificity and versatility [7]. The three steps of the ubiquitination process (Figure 1) have been reviewed previously [8,9]. Briefly, the activation step requires binding of both ATP and ubiquitin and links the α-carboxyl group of the C-terminal glycine residue of ubiquitin to a cysteine residue on E1, and a thioester linkage is formed between the u biquitin and E1.Then the E2 binds to both activated ubiquitin and the E1 enzyme and thus transfers the ubiquitin from E1 to the active site cysteine of the E2 via a trans(thio)esterification reaction. Finally, the E3 catalyzes the linking of ubiquitin to a lysine residue on the substrate. Repetitions of these sequential steps results in a long chains of ubiquitin (polyubiquitin) on the protein to be degraded, and the specific lysine residue on ubiquitin used for linking (e.g., K48, K63, etc.) results in different topologies [10]. Ubiquitination was originally described as a mechanism by which cells dispose of short-lived, damaged, or abnormal proteins, but more rece...

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Section: Future Perspectivementioning

confidence: 99%

Targeting Ubiquitination for Cancer Therapies

Morrow¹,

Lin

Sun

et al. 2015

Future Med. Chem.

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“…However, there are also an increasing number of intracellular immune checkpoints (Forkhead box protein P3 (Foxp3), Signal Transducer and Activator of Transcription 3 (STAT3), Casitas B-lineage Lymphoma-b (cbl-b), Early growth response proteins-2 (EGR-2), Src Homology region 2 domain-containing Phosphatase-1 (SHP1), Src Homology region 2 domain-containing Phosphatase-2 (SHP2), etc.) which are harder to be druggable [25,26,27,28,29,30,31,32,33,34]. …”

Section: Immune-checkpoint Antagonizing Aptamersmentioning

confidence: 99%

Aptamers: A New Technological Platform in Cancer Immunotherapy

Pastor

2016

Pharmaceuticals

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The renaissance of cancer immunotherapy is, nowadays, a reality. In the near future, it will be very likely among the first-line treatments for cancer patients. There are several different approaches to modulate the immune system to fight against tumor maladies but, so far, monoclonal antibodies may currently be the most successful immuno-tools used to that end. The number of ongoing clinical trials with monoclonal antibodies has been increasing exponentially over the last few years upon the Food and Drug Administration (FDA) approval of the first immune-checkpoint blockade antibodies. In spite of the proved antitumor effect of these reagents, the unleashing of the immune system to fight cancer cells has a cost, namely auto-inflammatory toxicity. Additionally, only a small fraction of all patients treated with immune-checkpoint antibodies have a clinical benefit. Taking into account all this, it is urgent new therapeutic reagents are developed with a contained toxicity that could facilitate the combination of different immune-modulating pathways to broaden the antitumor effect in most cancer patients. Based on preclinical data, oligonucleotide aptamers could fulfill this need. Aptamers have not only been successfully used as antagonists of immune-checkpoint receptors, but also as agonists of immunostimulatory receptors in cancer immunotherapy. The simplicity of aptamers to be engineered for the specific delivery of different types of cargos to tumor cells and immune cells so as to harvest an efficient antitumor immune response gives aptamers a significant advantage over antibodies. In this review all of the recent applications of aptamers in cancer immunotherapy will be described.

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“…Our group and others have characterized the role of the E3 ubiquitin ligase Casitas B lineage lymphoma b (Cbl-b) in the regulation of peripheral tolerance mechanisms through the interplay with multiple substrates associated with the T cell receptor (TCR) signalling pathway, such as protein kinase Cu (PKCu), phospholipase Cg1, Vav-1, the p85 subunit of phosphatidylinositol 3-kinase (PI3K-p85) and phosphatase and tensin homologue deleted on chromosome 10 (Pten). In murine models, Cblb deficiency has been implicated in the development of lupus-like disease, secondary to impaired peripheral tolerance mechanisms, such as anergy and suppression by T regs [19,[24][25][26][27][28][29][30].…”

Section: T Cells [2-4] Through Diverse Mechanisms Thatmentioning

confidence: 99%

Lys63-polyubiquitination by the E3 ligase casitas B-lineage lymphoma-b (Cbl-b) modulates peripheral regulatory T cell tolerance in patients with systemic lupus erythematosus

Romo-Tena

Aparicio‐Vera

Alcocer‐Varela

et al. 2017

Clinical and Experimental Immunology

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Summary T cells from systemic lupus erythematosus (SLE) patients display a wide array of anomalies in peripheral immune tolerance mechanisms. The role of ubiquitin ligases such as Cbl-b has been described recently in these phenomena. However, its role in resistance to suppression phenotype in SLE has not been characterized, which was the aim of the present study. Thirty SLE patients (20 with active disease and 10 with complete remission) and 30 age- and sex-matched healthy controls were recruited. Effector (CD4+CD25–) and regulatory (CD4+CD25+) T cells (Tregs) were purified from peripheral blood mononuclear cells (PBMCs) by magnetic selection. Suppression assays were performed in autologous and allogeneic co-cultures and analysed by a flow cytometry assay. Cbl-b expression and lysine-63 (K63)-specific polyubiquitination profile were assessed by Western blotting. We found a defective Cbl-b expression in Tregs from lupus patients in contrast to healthy controls (1·1 ± 0·9 versus 2·5 ± 1·8, P = 0·003), which was related with resistance to suppression (r = 0·633, P = 0·039). Moreover, this feature was associated with deficient K63 polyubiquitination substrates and enhanced expression of phosphorylated signal transducer and activation of transcription 3 (pSTAT-3) in Tregs from lupus patients. Our findings support that Cbl-b modulates resistance to suppression by regulating the K63 polyubiquitination profile in lupus Tregs. In addition, defective K63 polyubiquitination of STAT-3 is related to increased pSTAT-3 expression, and might promote the loss of suppressive capacity of Tregs in lupus patients.

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Modulation of Immune Cell Functions by the E3 Ligase Cbl-b

Cited by 71 publications

References 164 publications

Targeting Ubiquitination for Cancer Therapies

Targeting Ubiquitination for Cancer Therapies

Aptamers: A New Technological Platform in Cancer Immunotherapy

Lys63-polyubiquitination by the E3 ligase casitas B-lineage lymphoma-b (Cbl-b) modulates peripheral regulatory T cell tolerance in patients with systemic lupus erythematosus

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