Human ITCH E3 Ubiquitin Ligase Deficiency Causes Syndromic Multisystem Autoimmune Disease

Lohr, Naomi J.; Molleston, Jean P.; Strauss, Kevin A.; Torres-Martinez, Wilfredo; Sherman, Eric A.; Squires, Robert H.; Rider, Nicholas L.; Chikwava, Kudakwashe R.; Cummings, Oscar W.; Morton, D. Holmes; Puffenberger, Erik G.

doi:10.1016/j.ajhg.2010.01.028

Cited by 176 publications

(159 citation statements)

References 21 publications

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“…Although spontaneous tumors in human cases of Itch deficiency and in Itch mutant mice (Itchy mice) have not yet been reported (Perry et al, 1998;Lohr et al, 2010), no systematic studies have been undertaken to correlate Itch ablation with tumor development. Therefore, the Itch involvement in tumorigenesis remains unclear and needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal

et al. 2010

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Hedgehog pathway regulates tissue patterning and cell proliferation. Gli1 transcription factor is the major effector of Hedgehog signaling and its deregulation is often associated to medulloblastoma formation. Proteolytic processes represent a critical mechanism by which this pathway is turned off. Here, we characterize the regulation of an ubiquitin-mediated mechanism of Gli1 degradation, promoted by the coordinated action of the E3 ligase Itch and the adaptor protein Numb. We show that Numb activates the catalytic activity of Itch, releasing it from an inhibitory intramolecular interaction between its homologous to E6-AP C-terminus and WW domains. The consequent activation of Itch, together with the recruitment of Gli1 through direct binding with Numb, allows Gli1 to enter into the complex, resulting in Gli1 ubiquitination and degradation. This process is mediated by a novel Itch-dependent degron, composed of a combination of two PPXYs and a phospho-serine/proline motifs, localized in Gli1 C-terminal region, indicating the role of two different WW docking sites in Gli1 ubiquitination. Remarkably, Gli1 protein mutated in these modules is no longer regulated by Itch and Numb, and determines enhanced Gli1-dependent medulloblastoma growth, migration and invasion abilities, as well as in vitro transforming activity. Our data reveal a novel mechanism of regulation of Gli1 stability and function, which influences Hedgehog/Gli1 oncogenic potential. Oncogene (2011) 30, 65-76; doi: 10.1038/onc.2010.394; published online 6 September 201

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Section: Discussionmentioning

confidence: 99%

Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal

et al. 2010

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“…Autoimmune enteropathy was a frequent finding in many members of this family. 10 Single-nucleotide polymorphism mapping found all patients affected, harbored a truncating mutation in the ITCH gene. ITCH deficiency results in abnormal T helper cell differentiation and failed T-cell anergy induction.…”

Section: Discussionmentioning

confidence: 99%

“…Both patients with immunodysregulation polyendocrinopathy enteropathy X-linked syndrome and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy were confirmed to harbor mutations in the genes forkhead box P3 (FOXP3) and autoimmune regulatory (AIRE), respectively. In addition, the patient demonstrating ITCH deficiency was reported previously by Lohr et al 10 The patient belongs to large Amish kindred with a homozygous single base-pair insertion in exon 6 of the ITCH gene. Concurrent autoimmunerelated diseases included juvenile rheumatoid arthritis (n ¼ 2), autoimmune thyroiditis (n ¼ 2), celiac disease (n ¼ 2), autoimmune atrophic gastritis (n ¼ 1), autoimmune hepatitis (n ¼ 1) and asthma (n ¼ 1).…”

Section: Clinical and Serologic Findingsmentioning

confidence: 99%

Pediatric autoimmune enteropathy: an entity frequently associated with immunodeficiency disorders

et al. 2014

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The term pediatric autoimmune enteropathy was originally applied to a form of intractable diarrhea seen in children under the age of 6 months and characterized by male predominance, concurrent autoimmuneassociated disorders, circulating gut autoantibodies, a lack of severe immunodeficiency and small bowel atrophy with prominent crypt apoptosis. However, recent studies have cast doubt over the specific clinicopathologic findings associated with this entity. We, therefore, collected 178 gastrointestinal biopsies from 14 patients and examined their clinical, serologic and pathologic findings. Patients at presentation ranged in age from birth to 15.9 years (median, 5.5 months; mean, 4.1 years) and included six males and eight females. All children suffered from chronic watery diarrhea and malnutrition. Concomitant-associated disorders were noted in 11 (79%) cases and included 10 (71%) with an immunodeficiency disorder and/or another autoimmunerelated disease. Eleven patients (79%) were positive for anti-enterocyte antibodies. The salient findings of autoimmune enteropathy were most prominent in the small intestines and the majority (79%) of patients demonstrated villous blunting, crypt hyperplasia, mononuclear cell inflammatory expansion of the lamina propria and crypt apoptosis. The remaining (21%) patients showed marked intraepithelial lymphocytosis reminiscent of celiac disease. Further, acute cryptitis and crypt abscesses were seen in seven (50%) patients obscuring the presence of apoptosis. The absence of Paneth cells, goblet cells or both was noted in seven (50%) patients. Follow-up information was available for all patients with 13 (93%) receiving immunosuppressant therapy and demonstrating partial-to-complete response. In total, three patients died from continued diarrhea and sepsis with one decedent before treatment could be initiated. In summary, autoimmune enteropathy in children is a heterogenous disease with protean clinical and pathologic findings. Although anti-enterocyte antibodies were identified in the majority of the cases, their presence was variable and insensitive. In addition, pediatric autoimmune enteropathy was frequently encountered in the setting of immunodeficiency disorders.

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“…8 Accordingly, patients with Itch mutations have autoimmune inflammatory cell infiltration in various tissues. 9 Itch is also required for negative regulation of TNF-and lipopolysaccharide (LPS)-mediated TNF receptor-associated factor 6 (TRAF6) ubiquitylation induced RING finger protein 11 10 and represent a negative regulator of osteoclastogenesis by promoting de-ubiquitylation of TRAF6. 11 Moreover, like other HECTs, Itch is also deregulated in cancer development and represents a potential target for anticancer treatment.…”

Section: Introductionmentioning

confidence: 99%

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

et al. 2014

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Both in epithelial development as well as in epithelial cancers, the p53 family member p63 plays a crucial role acting as a master transcriptional regulator. P63 steady state protein levels are regulated by the E3 ubiquitin ligase Itch, via a physical interaction between the PPxY consensus sequence (PY motif) of p63 and one of the 4 WW domains of Itch; this substrate recognition process leads to protein-ubiquitylation and p63 proteasomal degradation. The interaction of the WW domains, a highly compact protein-protein binding module, with the short proline-rich sequences is therefore a crucial regulatory event that may offer innovative potential therapeutic opportunity. Previous molecular studies on the Itch-p63 recognition have been performed in vitro using the Itch-WW2 domain and the peptide interacting fragment of p63 (pep63), which includes the PY motif. Itch-WW2-pep63 interaction is also stabilized in vitro by the conformational constriction of the S-S cyclization in the p63 peptide. The PY motif of p63, as also for other proteins, is characterized by the nearby presence of a (T/S)P motif, which is a potential recognition site of the WW domain of the IV group present in the prolyl-isomerase Pin1. In this study, we demonstrate, by in silico and spectroscopical studies using both the linear pep63 and its cyclic form, that the threonine phosphorylation of the (T/S)PPPxY motif may represent a crucial regulatory event of the Itch-mediated p63 ubiquitylation, increasing the Itch-WW domains-p63 recognition event and stabilizing in vivo the Itch-WW-p63 complex. Moreover, our studies confirm that the subsequently trans/cis proline isomerization of (T/S)P motif by the Pin1 prolyl-isomerase, could modulate the E3-ligase interaction, and that the (T/S) p P trans PPxY motif represent the best conformer for the ItchWW-(T/S)PPPxY motif recognition.

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Human ITCH E3 Ubiquitin Ligase Deficiency Causes Syndromic Multisystem Autoimmune Disease

Cited by 176 publications

References 21 publications

Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal

Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal

Pediatric autoimmune enteropathy: an entity frequently associated with immunodeficiency disorders

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

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