The E3 ligase Itch in immune regulation and beyond

Aki, Daisuke; Zhang, Wen; Liu, Yun‐Cai

doi:10.1111/imr.12301

Cited by 56 publications

(47 citation statements)

References 224 publications

(332 reference statements)

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“…Beyond the essential function in the control of immune system, Itch is also implicated in other biological processes, including development, tumorigenesis, and stress responses [45,46]. Most of these findings were made in an Itch-deficient context, for example, the Itch À/À Itchy mice.…”

Section: Activation Of Itch Promotes Neuronal Migration In the Develomentioning

confidence: 99%

Allosteric auto‐inhibition and activation of the Nedd4 family E3 ligase Itch

et al. 2017

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The Nedd4 family E3 ligases are key regulators of cell growth and proliferation and are often misregulated in human cancers and other diseases. The ligase activities of Nedd4 E3s are tightly controlled via auto-inhibition. However, the molecular mechanism underlying Nedd4 E3 auto-inhibition and activation is poorly understood. Here, we show that the WW domains proceeding the catalytic HECT domain play an inhibitory role by binding directly to HECT in the Nedd4 E3 family member Itch. Our structural and biochemical analyses of Itch reveal that the WW2 domain and a following linker allosterically lock HECT in an inactive state inhibiting E2-E3 transthiolation. Binding of the Ndfip1 adaptor or JNK1-mediated phosphorylation relieves the auto-inhibition of Itch in a WW2-dependent manner. Aberrant activation of Itch leads to migration defects of cortical neurons during development. Our study provides a new mechanism governing the regulation of Itch.

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Section: Activation Of Itch Promotes Neuronal Migration In the Develomentioning

confidence: 99%

Allosteric auto‐inhibition and activation of the Nedd4 family E3 ligase Itch

et al. 2017

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“…Members of the NEDD4 family include WWP2, WWP1, ITCH, and NEDD4-1 and these E3 ligases target for destruction key signaling molecules and transcription factors (Aki et al, 2015; Buetow and Huang, 2016; Chen et al, 2014; Scheffner and Kumar, 2014; Zhi and Chen, 2012). Abnormal activities of NEDD4 E3 ligases are connected to cancer, immune disorders, and other diseases (Aki et al, 2015; Broix et al, 2016; Buetow and Huang, 2016; Chen et al, 2014; Scheffner and Kumar, 2014; Zhi and Chen, 2012). The NEDD4 family proteins each contain an N-terminal C2 domain followed by two to four WW domains and culminate in a C-terminal catalytic HECT domain (Figure 1A and Figure S1A) (Buetow and Huang, 2016).…”

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confidence: 99%

A Tunable Brake for HECT Ubiquitin Ligases

et al. 2017

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The HECT E3 ligases ubiquitinate numerous transcription factors and signaling molecules and their activity must be tightly controlled to prevent cancer, immune disorders, and other diseases. In this study we have found unexpectedly that peptide linkers tethering WW domains in several HECT family members are key regulatory elements of their catalytic activities. Biochemical, structural, and cellular analysis has revealed that the linkers can lock the HECT domain in an inactive conformation and block the proposed allosteric ubiquitin binding site. Such linker-mediated autoinhibition of the HECT domain can be relieved by linker post-translational modifications, but complete removal of the brake can induce hyperactive autoubiquitination and E3 self-destruction. These results clarify the mechanisms of several HECT protein cancer associated mutations and provide a new framework for understanding how HECT ubiquitin ligases must be finely tuned to ensure normal cellular behavior.

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“…10 Further evidence showed that tissue alterations such as abnormal dermal proliferation and tumor proliferation first identified in itchy mice, manifest similarly in humans with Itch polymorphisms. 9,11,12 These findings justify further patho-physiological analyses of itchy mice and identifications of novel physiologic pathways affected by ITCH.…”

Section: Introductionmentioning

confidence: 75%

“…Both helper T cells 9 and macrophages 32 are alternatively polarized in itchy mice. The biased differentiation of leukocytes in itchy mice may account for the pathologic female reproductive function.…”

Section: Discussionmentioning

confidence: 99%

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Featured Article: Female mice with loss-of-function ITCH display an altered reproductive phenotype

Stermer

Myers

Murphy

et al. 2015

Exp Biol Med (Maywood)

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Major progress in deciphering the role of the E3 ligase, ITCH, in animal physiology has come from the generation and identification of Itch loss-of-function mutant mice (itchy). Mutant mice display an autoimmune-like phenotype characterized by chronic dermatitis, which has been attributed to increased levels of ITCH target proteins (e.g. transcription factors JUNB and CJUN) in T cells. Autoimmune disorders also exist in humans with Itch frameshift mutations resulting in loss of functional ITCH protein. Recent phenotypic analysis of male itchy mice revealed reduced sperm production, although cross breeding experiments showed no difference in litter size when male itchy mice were bred to wild type females. However, a reduction in litter sizes did occur when itchy females were bred to wild type males. Based on these results, characterization of female reproductive function in itchy mice was performed. Developmental analysis of fetuses at gestational day 18.5, cytological evaluation of estrous cyclicity, histopathological analysis of ovaries, and protein analysis were used to investigate the itchy reproductive phenotype. Gross skeletal and soft tissue analysis of gestational day 18.5 itchy fetuses indicated no gross developmental deformities. Itchy females had reduced implantation sites, decreased corpora lutea, and increased estrous cycle length due to increased number of days in estrus compared to controls. Alterations in the expression of prototypical ITCH targets in the ovaries were not indicated, suggesting that an alteration in an as yet defined ovary-specific ITCH substrate or interaction with the altered immune system likely accounts for the disruption of female reproduction. This report indicates the importance of the E3 ligase, ITCH, in female reproduction.

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The E3 ligase Itch in immune regulation and beyond

Cited by 56 publications

References 224 publications

Allosteric auto‐inhibition and activation of the Nedd4 family E3 ligase Itch

Allosteric auto‐inhibition and activation of the Nedd4 family E3 ligase Itch

A Tunable Brake for HECT Ubiquitin Ligases

Featured Article: Female mice with loss-of-function ITCH display an altered reproductive phenotype

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