Itch: a HECT-type E3 ligase regulating immunity, skin and cancer

Melino, Gerry; Gallagher, Ewen; Aqeilan, Rami I.; Knight, Richard; Peschiaroli, Angelo; Rossi, Mario; Scialpi, Flavia; Malatesta, Martina; Zocchi, Loredana; Browne, Gareth J.; Ciechanover, Aaron; Bernassola, Francesca

doi:10.1038/cdd.2008.60

Cited by 155 publications

(146 citation statements)

References 63 publications

(107 reference statements)

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“…Itch function was proposed to be regulated at the point of substrate recognition through its WW domains and via intramolecular autoinhibition (32). The autoinhibitory interaction between the WW domains and the HECT domain could prevent E2 binding or inhibit the transthiolation reaction between E2 and E3 (42).…”

Section: Discussionmentioning

confidence: 99%

“…By virtue of its target substrates, Itch plays a crucial role in inflammatory signaling pathways (32,37), but how its function is controlled remains unclear. In this article, we demonstrate that Itch ligase activity is regulated by Ndfip1 by facilitating the recruitment of the E2 enzyme UbcH7.…”

Section: Discussionmentioning

confidence: 99%

“…Itch ligase activity was shown to be enhanced by JNK1-mediated phosphorylation (32,33). Because Itch is a HECT-type E3 ligase, which requires the formation of a thioester covalent attachment of Ub to a highly conserved cysteine residue in its HECT domain by the E2 enzyme (5), we hypothesized that Ndfip1 may regulate Itch ligase activity by recruiting Ub-loaded E2.…”

Section: Ndfip1 Acts As An Adaptor For Ubch7 and Itchmentioning

confidence: 99%

“…The function of Itch is believed to be regulated at the point of substrate recognition through the WW domains (32). Itch ligase activity was shown to be enhanced by JNK1-mediated phosphorylation (32,33).…”

Section: Ndfip1 Acts As An Adaptor For Ubch7 and Itchmentioning

confidence: 99%

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Ndfip1 Regulates Itch Ligase Activity and Airway Inflammation via UbcH7

Kathania

Zeng

Yadav

et al. 2015

The Journal of Immunology

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The ubiquitin-ligating enzyme (E3) Itch plays a crucial role in the regulation of inflammation, and Itch deficiency leads to severe airway inflammation. However, the molecular mechanisms by which Itch function is regulated remain elusive. In this study, we found that nontypeable Haemophilus influenzae induces the association of Itch with Ndfip1. Both Itch−/− and Ndfip1−/− mice exhibited severe airway inflammation in response to nontypeable Haemophilus influenza, which was associated with elevated expression of proinflammatory cytokines. Ndfip1 enhanced Itch ligase activity and facilitated Itch-mediated Tak1 ubiquitination. Mechanistically, Ndfip1 facilitated recruitment of ubiquitin-conjugating enzyme (E2) UbcH7 to Itch. The N-terminal region of Ndfip1 binds to UbcH7, whereas the PY motif binds to Itch. Hence, Ndfip1 acts as an adaptor for UbcH7 and Itch. Reconstitution of full-length Ndfip1 but not the mutants that fail to interact with either UbcH7 or Itch, restored the defect in Tak1 ubiquitination and inhibited elevated proinflammatory cytokine expression by Ndfip1−/− cells. These results provide new mechanistic insights into how Itch function is regulated during inflammatory signaling, which could be exploited therapeutically in inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ndfip1 Acts As An Adaptor For Ubch7 and Itchmentioning

confidence: 99%

Section: Ndfip1 Acts As An Adaptor For Ubch7 and Itchmentioning

confidence: 99%

See 2 more Smart Citations

Ndfip1 Regulates Itch Ligase Activity and Airway Inflammation via UbcH7

Kathania

Zeng

Yadav

et al. 2015

The Journal of Immunology

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“…However, as Itch is ubiquitously expressed, the contribution of other cellular and molecular Itch-dependent mechanisms to this complex phenotype cannot be excluded. Indeed, Itch deficiency can also affect the differentiation of epidermal keratinocytes and gd T-cell-dependent IgE production [49,50].…”

Section: Itchmentioning

confidence: 99%

E3 ubiquitin ligases in T‐cell tolerance

Paolino

Penninger

2009

Eur J Immunol

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The immune system uses several mechanisms of central and peripheral tolerance in order to prevent the activation of T lymphocytes toward self-antigens. Although the importance of immune self-tolerance has been established for a long time, some essential cellular and molecular mechanisms of T-cell tolerance have only been recently revealed. Once thought to be a recycling system, protein ubiquitylation by E3 ligases has now emerged as a regulated and crucial modulator of immune responses, and more importantly as a key signaling pathway involved in T-cell tolerance. In this review, we highlight our current understanding of the transcriptional and molecular signaling mechanisms involved in ubiquitylation-mediated T-cell tolerance.Key words: Autoimmunity . Cbl-b . E3 ligase . T-cell tolerance . Ubiquitylation IntroductionUpon activation, the immune system orchestrates robust and potentially destructive responses intended to eliminate the immunogenic antigen. Thus, immune system activation is under stringent control to prevent a detrimental immune response against self-antigens. The processes that ensure unresponsiveness toward self-antigens are known as immunological tolerance and, in their absence or failure, autoimmunity occurs [1]. Central tolerance mechanisms operate in the thymus to eliminate potentially self-reactive thymocytes and generate (T reg ) suppressor cells [2]. In addition, several peripheral tolerance mechanisms act to prevent self-reactivity once mature T cells have reached the periphery. These peripheral mechanisms of tolerance include the following: (i) immunological ignorance to selfantigens expressed at low levels or in immunoprivileged sites; (ii) active immunosuppression by Foxp31 T reg cells; (iii) activation-induced cell death of autoreactive T cells and (iv) induction of a state of unresponsiveness known as T-cell anergy [3].During the past few years, extensive research has revealed new insights into the cellular and molecular mechanisms necessary to induce and maintain T-cell tolerance. In particular, ubiquitylation of proteins by E3 ligases has emerged as a novel and indispensable signaling pathway that regulates T-cell tolerance toward self-antigens [4][5][6]. The ubiquitylation processUbiquitylation is an important mechanism of post-translational modification of proteins by which the 76-aa polypeptide ubiquitin, Ub, is covalently attached to a substrate protein. This process occurs in a stepwise manner, requiring the participation of three enzymes: a ubiquitin-activating enzyme E1, responsible for the first binding and activation of the Ub; a second ubiquitinconjugating enzyme E2, which receives the activated Ub from the E1; and a third ubiquitin-ligase E3 that catalyzes the final covalent transfer of the Ub from the E2 enzyme to the protein substrate [7]. Once thought to only mediate proteosomal degradation, the ubiquitylation of a protein can have multiple effects, including altered subcellular localization, regulation of protein-protein interactions, and functional modulation. The fa...

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Emerging roles of HECT‐type E3 ubiquitin ligases in autophagy regulation

et al. 2019

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Autophagy is a conserved self‐eating process that delivers cytoplasmic material to the lysosome to allow degradation of intracellular components, including soluble, unfolded and aggregated proteins, damaged organelles, and invading microorganisms. Autophagy provides a homeostatic control mechanism and is essential for balancing sources of energy in response to nutrient stress. Autophagic dysfunction or dysregulation has been implicated in several human pathologies, including cancer and neurodegeneration, and its modulation has substantial potential as a therapeutic strategy. Given the relevant clinical and therapeutic implications of autophagy, there is emerging intense interest in the identification of the key factors regulating the components of the autophagic machinery. Various post‐translational modifications, including ubiquitylation, have been implicated in autophagy control. The list of the E3 ubiquitin protein ligases involved in the regulation of several steps of the autophagic process is continuously growing. In this review, we will focus on recent advances in the understanding of the role of the homologous to the E6AP carboxyl terminus‐type E3 ubiquitin ligases in autophagy control.

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Itch: a HECT-type E3 ligase regulating immunity, skin and cancer

Cited by 155 publications

References 63 publications

Ndfip1 Regulates Itch Ligase Activity and Airway Inflammation via UbcH7

Ndfip1 Regulates Itch Ligase Activity and Airway Inflammation via UbcH7

E3 ubiquitin ligases in T‐cell tolerance

Emerging roles of HECT‐type E3 ubiquitin ligases in autophagy regulation

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