Regulation of Treg Functions by the Ubiquitin Pathway

Montauti, Elena; Fang, Deyu

doi:10.1007/978-981-15-6407-9_3

Cited by 1 publication

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“…The balance between E3 ligases and DUBs on Foxp3 expression results in an equilibrium state that regulates Foxp3 levels within T reg cells. We and others have discovered three members of the ubiquitin-specific peptidase (USP) family as direct modulators of Foxp3 deubiqutination at the transcriptional and/or posttranslational level: Usp7, Usp21, and Usp22 (12)(13)(14)(15)(16). However, the broad environmental cues and cellular regulation of these deubiquitinases remain unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Foxp3 expression and stability can be regulated from the transcriptional to the posttranslational level, with each layer independently controlling the stability and overall function of T reg cells. In particular, a newly appreciated layer of Foxp3 regulation and T reg functional modulation is through ubiquitination ( 12 , 13 ). Ubiquitination of histones on the Foxp3 promoter and conserved noncoding DNA sequence regions via E3 ubiquitin ligases results in chromatin condensation and lack of Foxp3 transcription ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

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A deubiquitination module essential for T _reg fitness in the tumor microenvironment

et al. 2022

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The tumor microenvironment (TME) enhances regulatory T (T reg ) cell stability and immunosuppressive functions through up-regulation of lineage transcription factor Foxp3, a phenomenon known as T reg fitness or adaptation. Here, we characterize previously unknown TME-specific cellular and molecular mechanisms underlying T reg fitness. We demonstrate that TME-specific stressors including transforming growth factor–β (TGF-β), hypoxia, and nutrient deprivation selectively induce two Foxp3-specific deubiquitinases, ubiquitin-specific peptidase 22 ( Usp22 ) and Usp21 , by regulating TGF-β, HIF, and mTOR signaling, respectively, to maintain T reg fitness. Simultaneous deletion of both USPs in T reg cells largely diminishes TME-induced Foxp3 up-regulation, alters T reg metabolic signatures, impairs T reg -suppressive function, and alleviates T reg suppression on cytotoxic CD8 + T cells. Furthermore, we developed the first Usp22 -specific small-molecule inhibitor, which dramatically reduced intratumoral T reg Foxp3 expression and consequently enhanced antitumor immunity. Our findings unveil previously unappreciated mechanisms underlying T reg fitness and identify Usp22 as an antitumor therapeutic target that inhibits T reg adaptability in the TME.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A deubiquitination module essential for T _reg fitness in the tumor microenvironment

et al. 2022

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Regulation of Treg Functions by the Ubiquitin Pathway

Cited by 1 publication

References 122 publications

A deubiquitination module essential for T _reg fitness in the tumor microenvironment

A deubiquitination module essential for T _reg fitness in the tumor microenvironment

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Regulation of Treg Functions by the Ubiquitin Pathway

Cited by 1 publication

References 122 publications

A deubiquitination module essential for T reg fitness in the tumor microenvironment

A deubiquitination module essential for T reg fitness in the tumor microenvironment

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A deubiquitination module essential for T _reg fitness in the tumor microenvironment

A deubiquitination module essential for T _reg fitness in the tumor microenvironment