Integrative proteomics reveals an increase in non-degradative ubiquitylation in activated CD4+ T cells

Dybas, Joseph M.; O’Leary, Claire E.; Ding, Hua; Spruce, Lynn A.; Seeholzer, Steven H.; Oliver, Paula

doi:10.1038/s41590-019-0381-6

Cited by 29 publications

(25 citation statements)

References 55 publications

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“…We initially identified Cul4b in a screen that used di-glycine remnant profiling [ 28 , 29 ] in a manner that revealed cullin ligases that were particularly active (neddylated) in T cells following TCR ligation [ 30 ]. The covalent attachment of Nedd8 (“neddylation”) of a cullin E3 ligase induces a conformational change in the CRL complex that increases its enzymatic activity [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

The E3 ubiquitin ligase Cul4b promotes CD4+ T cell expansion by aiding the repair of damaged DNA

et al. 2021

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The capacity for T cells to become activated and clonally expand during pathogen invasion is pivotal for protective immunity. Our understanding of how T cell receptor (TCR) signaling prepares cells for this rapid expansion remains limited. Here we provide evidence that the E3 ubiquitin ligase Cullin-4b (Cul4b) regulates this process. The abundance of total and neddylated Cul4b increased following TCR stimulation. Disruption of Cul4b resulted in impaired proliferation and survival of activated T cells. Additionally, Cul4b-deficient CD4+ T cells accumulated DNA damage. In T cells, Cul4b preferentially associated with the substrate receptor DCAF1, and Cul4b and DCAF1 were found to interact with proteins that promote the sensing or repair of damaged DNA. While Cul4b-deficient CD4+ T cells showed evidence of DNA damage sensing, downstream phosphorylation of SMC1A did not occur. These findings reveal an essential role for Cul4b in promoting the repair of damaged DNA to allow survival and expansion of activated T cells.

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Section: Resultsmentioning

confidence: 99%

The E3 ubiquitin ligase Cul4b promotes CD4+ T cell expansion by aiding the repair of damaged DNA

et al. 2021

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“…Ubiquitylation signals regulate multiple aspects of immune cell function and immune response (134). Upon T cell activation, the non-degradative ubiquitylation, including K29, K33, and K63 polyubiquitylation, increases largely in CD4 + T cells, which suggests the importance of non-degradative ubiquitylation in T cell signaling (135).…”

Section: Post-translational Modifications Of Foxp3mentioning

confidence: 99%

Foxp3 Post-translational Modifications and Treg Suppressive Activity

et al. 2019

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Regulatory T cells (Tregs) are engaged in maintaining immune homeostasis and preventing autoimmunity. Treg cells include thymic Treg cells and peripheral Treg cells, both of which can suppress the immune response via multiple distinct mechanisms. The differentiation, proliferation, suppressive function and survival of Treg cells are affected by distinct energy metabolic programs. Tissue-resident Treg cells hold unique features in comparison with the lymphoid organ Treg cells. Foxp3 transcription factor is a lineage master regulator for Treg cell development and suppressive activity. Accumulating evidence indicates that the activity of Foxp3 protein is modulated by various post-translational modifications (PTMs), including phosphorylation, O-GlcNAcylation, acetylation, ubiquitylation and methylation. These modifications affect multiple aspects of Foxp3 function. In this review, we define features of Treg cells and roles of Foxp3 in Treg biology, and summarize current research in PTMs of Foxp3 protein involved in modulating Treg function. This review also attempts to define Foxp3 dimer modifications relevant to mediating Foxp3 activity and Treg suppression. Understanding Foxp3 protein features and modulation mechanisms may help in the design of rational therapies for immune diseases and cancer.

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“…The present work provided novel knowledge to the functions of LLPUC of K33, which is still largely unknown 27,38,39 . LLPUC of K33 has also been reported conjugating p62 for aggresome formation 27,40 .…”

Section: Discussionmentioning

confidence: 99%

Opposite Regulation of F508del-CFTR Biogenesis by Four Poly-Lysine Ubiquitin Chains

Henri

Yao

et al. 2020

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Background: As a misfolding protein, more than 99% of F508del-CFTR (F508del) is degraded by the ubiquitin-proteasome system before its maturation, which results in almost no membrane expression of CFTR and thereby no chloride secretion across epithelial cells of cystic fibrosis patients. The conjugation of ubiquitin chains to the protein substrates is necessary for ubiquitin-mediated proteasomal degradation. Ubiquitin contains seven lysine (K) residues (K6, K11, K27, K29, K33, K48, and K63), all of them can be conjugated one to another forming poly-ubiquitin chains on substrates by mixing together or by only one type of lysine that provides sorting signals for different pathways. Results: Here we report that four lysine linked poly-Ub chains (LLPUCs) were involved in F508del biogenesis: two LLPUCs linked by K11 or K48 of Ub facilitated F508del degradation; whereas the other two linked by K63 and K33 of Ub protected F508del from degradation. LLPUC K11 is more potent for F508del degradation than K48. Moreover, E3 ligase CHIP and RNF5 catalyzed LLPUCs K48 formation and RNF5 also catalyzed LLPUC K11 formation on F508del. Importantly, Those LLPUCs provide F508del with different affinities to the proteasomal shuttle protein (Rad23a) and the proteasomal receptors (Adrm1 and S5a), offering a mechanistic insight of differential regulation F508del different by different LLPUCs. Conclusions: F508del utilizes four specific lysine-linked poly Ub chains and during its biogenesis for opposite destiny through different identification by proteasomal shuttle protein or receptors. These findings provide new insights to understand the CF pathogenesis and are expected to facilitate the development of therapies for this devastating disease.

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Integrative proteomics reveals an increase in non-degradative ubiquitylation in activated CD4+ T cells

Cited by 29 publications

References 55 publications

The E3 ubiquitin ligase Cul4b promotes CD4+ T cell expansion by aiding the repair of damaged DNA

The E3 ubiquitin ligase Cul4b promotes CD4+ T cell expansion by aiding the repair of damaged DNA

Foxp3 Post-translational Modifications and Treg Suppressive Activity

Opposite Regulation of F508del-CFTR Biogenesis by Four Poly-Lysine Ubiquitin Chains

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