Ubiquitination system and autoimmunity: The bridge towards the modulation of the immune response

Gómez‐Martín, Diana; Díaz-Zamudio, Mariana; Alcocer‐Varela, Jorge

doi:10.1016/j.autrev.2007.11.026

Cited by 39 publications

(27 citation statements)

References 39 publications

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“…Recently, it has been emerging that E3 ligases play an important function in regulating T-cell tolerance and immunity (reviewed in Bhoj and Chen, 2009;Deshaies and Joazeiro, 2009;Gomez-Martin et al, 2008). For instance, the E3 ligase c-Cbl regulates T-cell receptor (TCR) activation by both degrading key signalling molecules such as PLCc-1 (Jeon et al, 2004) and controlling TCR internalization and transport to the lysosomes (Naramura et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Ligand of Numb proteins LNX1p80 and LNX2 interact with the human glycoprotein CD8α and promote its ubiquitylation and endocytosis

D’Agostino

Tornillo

Caporaso

et al. 2011

Journal of Cell Science

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SummaryE3 ubiquitin ligases give specificity to the ubiquitylation process by selectively binding substrates. Recently, their function has emerged as a crucial modulator of T-cell tolerance and immunity. However, substrates, partners and mechanism of action for most E3 ligases remain largely unknown. In this study, we identified the human T-cell co-receptor CD8 a-chain as binding partner of the ligand of Numb proteins X1 (LNX1p80 isoform) and X2 (LNX2). Both LNX mRNAs were found expressed in T cells purified from human blood, and both proteins interacted with CD8a in human HPB-ALL T cells. By using an in vitro assay and a heterologous expression system we showed that the interaction is mediated by the PDZ (PSD95-DlgA-ZO-1) domains of LNX proteins and the cytosolic C-terminal valine motif of CD8a. Moreover, CD8a redistributed LNX1 or LNX2 from the cytosol to the plasma membrane, whereas, remarkably, LNX1 or LNX2 promoted CD8a ubiquitylation, downregulation from the plasma membrane, transport to the lysosomes, and degradation. Our findings highlight the function of LNX proteins as E3 ligases and suggest a mechanism of regulation for CD8a localization at the plasma membrane by ubiquitylation and endocytosis.

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Section: Introductionmentioning

confidence: 99%

Ligand of Numb proteins LNX1p80 and LNX2 interact with the human glycoprotein CD8α and promote its ubiquitylation and endocytosis

D’Agostino

Tornillo

Caporaso

et al. 2011

Journal of Cell Science

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“…Recently, it was hypothesized that the ubiquitination system and the cell's own proteolysis system were both in a close relationship with the equilibrium between immunity and tolerance [18]. However, these new experimental findings are, so far, not well understood.…”

Section: Discussionmentioning

confidence: 98%

In vitro model for the activation of CD4 and CD8 T cell receptors

Arneth¹

2009

Human Immunology

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“…The conjugation of ubiquitin mainly to a lysine residue from a protein substrate involves three subsequential enzymatic reactions, including the action of activating enzyme (E1), conjugating enzyme (E2) and finally ligase (E3), which is the enzyme that provides specificity to the system. Current evidence supports the role of ubiquitination as a PTM whose outcome can be dependent or independent of proteosomal or lysosomal degradation [18][19][20]. In particular, in immune response regulation, proteolysis-independent mechanisms, such as inhibition of phosphorylation, have been described [21,22].…”

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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Ubiquitination system and autoimmunity: The bridge towards the modulation of the immune response

Cited by 39 publications

References 39 publications

Ligand of Numb proteins LNX1p80 and LNX2 interact with the human glycoprotein CD8α and promote its ubiquitylation and endocytosis

Ligand of Numb proteins LNX1p80 and LNX2 interact with the human glycoprotein CD8α and promote its ubiquitylation and endocytosis

In vitro model for the activation of CD4 and CD8 T cell receptors

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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