The Ubiquitin/UBL Drug Target Repertoire

Osborne, Hugh C.; Irving, Elsa; Schmidt, Christine K.

doi:10.1016/j.molmed.2020.08.009

Cited by 4 publications

(3 citation statements)

References 10 publications

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“…The ubiquitin proteasome system (UPS) is a PTM mechanism involving a series of reactions catalyzed by three enzymes (E1 to E3). E3s mediate the last step by recognizing and catalyzing the transfer of ubiquitin to target proteins ( 49 ). On the basis of findings from a previous investigation ( 50 ), we identified aberrancies in the E3 ubiquitin ligase SKP2 in T cells.…”

Section: Resultsmentioning

confidence: 99%

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 ⁺ T cells

Celada,

Lim,

Carisey

et al. 2023

Sci. Transl. Med.

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Sarcoidosis is an interstitial lung disease (ILD) characterized by interferon-γ (IFN-γ) and T-box expressed in T cells (TBET) dysregulation. Although one-third of patients progress from granulomatous inflammation to severe lung damage, the molecular mechanisms underlying this process remain unclear. Here, we found that pharmacological inhibition of phosphorylated SH2-containing protein tyrosine phosphatase-2 (pSHP2), a facilitator of aberrant IFN-γ abundance, decreased large granuloma formation and macrophage infiltration in the lungs of mice with sarcoidosis-like disease. Positive treatment outcomes were dependent on the effective enhancement of TBET ubiquitination within CD8 + T cells. Mechanistically, we identified a posttranslational modification pathway in which the E3 F-box protein S-phase kinase–associated protein 2 (SKP2) targets TBET for ubiquitination in T cells under normal conditions. However, this pathway was disrupted by aberrant pSHP2 signaling in CD8 + T cells from patients with progressive pulmonary sarcoidosis and end-stage disease. Ex vivo inhibition of pSHP2 in CD8 + T cells from patients with end-stage sarcoidosis enhanced TBET ubiquitination and suppressed IFN-γ and collagen synthesis. Therefore, these studies provided new mechanistic insights into the SHP2-dependent posttranslational regulation of TBET and identified SHP2 inhibition as a potential therapeutic intervention against severe sarcoidosis. Furthermore, these studies also suggest that the small-molecule SHP2 inhibitor SHP099 might be used as a therapeutic measure against human diseases linked to TBET or ubiquitination.

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Section: Resultsmentioning

confidence: 99%

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 ⁺ T cells

Celada,

Lim,

Carisey

et al. 2023

Sci. Transl. Med.

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“…Finally, we note that our work may have medical applications as targeting DDR and ubiquitin/UBL system components can be exploited to treat cancer 124,125 . Indeed, targeting NHEJ at the level of XRCC4 interactions represents an attractive and actively pursued approach to sensitise cancer cells, commonly displaying cryptic DNA repair pathway defects including NHEJ, via synthetic lethality and/or other mechanisms 126,127 .…”

Section: Discussionmentioning

confidence: 99%

Microarray screening reveals a non-conventional SUMO-binding mode linked to DNA repair by non-homologous end-joining

Cabello-Lobato

Jenner

Loc’h³

et al. 2021

Preprint

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SUMOylation is critical for a plethora of cellular signalling pathways including the repair of DNA double-strand breaks (DSBs). If misrepaired, DSBs can lead to cancer, neurodegeneration, immunodeficiency and premature ageing. Based on systematic proteome microarray screening combined with widely applicable carbene footprinting and high-resolution structural profiling, we define two non-conventional SUMO2-binding modules on XRCC4, a DNA repair protein important for DSB repair by non-homologous end-joining (NHEJ). Mechanistically, interaction of SUMO2 with XRCC4 is incompatible with XRCC4 binding to at least two other NHEJ proteins – XLF and DNA ligase 4 (LIG4). These findings are consistent with SUMO2 interactions of XRCC4 acting as backup pathways at different stages of NHEJ, in the absence of these factors or their dysfunctioning. Such scenarios are not only relevant for carcinogenesis, but also for the design of precision anti-cancer medicines and the optimisation of CRISPR/Cas9-based gene editing. This work reveals insights into topology-specific SUMO recognition and its potential for modulating DSB repair by NHEJ. Moreover, it provides a rich resource on binary SUMO receptors that can be exploited for uncovering regulatory layers in a wide array of cellular processes.

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“…It is therefore not surprising that deregulation of ubiquitin and UBL systems are linked to a wide variety of human diseases, including cancer and neurodegenerative disorders as well as immune and inflammatory diseases [ 6 , 7 , 8 ]. As a consequence, components of the ubiquitin/UBL systems represent attractive drug targets for treating these diseases [ 9 ]. Although the involvement of ubiquitin, SUMO and NEDD8 in genotoxic stress responses is well established [ 3 , 10 , 11 ], the roles of the remaining UBLs in this regard are only starting to emerge [ 12 , 13 ].…”

Section: Ubiquitin and Ubiquitin-like Proteins (Ubls)—an Overviewmentioning

confidence: 99%

More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond

2020

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Maintenance of genome stability is a crucial priority for any organism. To meet this priority, robust signalling networks exist to facilitate error-free DNA replication and repair. These signalling cascades are subject to various regulatory post-translational modifications that range from simple additions of chemical moieties to the conjugation of ubiquitin-like proteins (UBLs). Interferon Stimulated Gene 15 (ISG15) is one such UBL. While classically thought of as a component of antiviral immunity, ISG15 has recently emerged as a regulator of genome stability, with key roles in the DNA damage response (DDR) to modulate p53 signalling and error-free DNA replication. Additional proteomic analyses and cancer-focused studies hint at wider-reaching, uncharacterised functions for ISG15 in genome stability. We review these recent discoveries and highlight future perspectives to increase our understanding of this multifaceted UBL in health and disease.

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The Ubiquitin/UBL Drug Target Repertoire

Cited by 4 publications

References 10 publications

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 ⁺ T cells

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 ⁺ T cells

Microarray screening reveals a non-conventional SUMO-binding mode linked to DNA repair by non-homologous end-joining

More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond

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The Ubiquitin/UBL Drug Target Repertoire

Cited by 4 publications

References 10 publications

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 + T cells

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 + T cells

Microarray screening reveals a non-conventional SUMO-binding mode linked to DNA repair by non-homologous end-joining

More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond

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SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 ⁺ T cells

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 ⁺ T cells