The E3 ubiquitin ligase Itch inhibits p38α signaling and skin inflammation through the ubiquitylation of Tab1

Theivanthiran, Balamayooran; Kathania, Mahesh; Zeng, Minghui; Anguiano, Esperanza; Basrur, Venkatesha; Vandergriff, Travis; Pascual, Virginia; Wei, Wei Zen; Massoumi, Ramin; Venuprasad, K.

doi:10.1126/scisignal.2005903

Cited by 39 publications

(37 citation statements)

References 65 publications

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“…Itch also regulates phosphorylation of the tumor suppressor p38α in response to stimulation with the cytokine TNF through the ubiquitination of the binding partner Tab1 (ref. 24). Thus, we have not excluded the possibility of a contribution by additional Itch-regulated pathways on the severe colitis and increased susceptibility for development of colon cancer in Itch −/− mice.…”

Section: Discussionmentioning

confidence: 84%

“…6b). Given that Itch deficiency also leads to spontaneous skin inflammation 24 ; we analyzed Il17 expression in the skin tissue of Itch −/− mice. However, we did not see elevated Il17 expression in the inflamed skin tissue of Itch −/− mice ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, we have not excluded the possibility of a contribution by additional Itch-regulated pathways on the severe colitis and increased susceptibility for development of colon cancer in Itch −/− mice. In addition, Itch has been shown to regulate inflammatory signaling in innate immune cells 24,28 . Although our data indicated that the adoptive transfer of Itch −/− CD4 + CD45RB hi cells led to severe colitis in Rag1 −/− mice, this does not completely rule out the possibility of a contribution from other immune cells.…”

Section: Discussionmentioning

confidence: 99%

“…This finding suggested that Itch targeted ROR-γt for ubiquitination. To confirm the specificity of Itch as the ligase, we used an ligase-defective Itch mutant in which a conserved catalytic cysteine is replaced with alanine (Itch-C830A) 24,28 . Expression of the Itch-C830A mutant with ROR-γt did not result in its ubiquitination (Fig.…”

Section: Itch Targets Ror-gt For Ubiquitinationmentioning

confidence: 99%

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Itch inhibits IL-17-mediated colon inflammation and tumorigenesis by ROR-γt ubiquitination

et al. 2016

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Dysregulated expression of interleukin 17 (IL-17) in the colonic mucosa is associated with colonic inflammation and cancer. However, the cell-intrinsic molecular mechanisms by which IL-17 expression is regulated remain unclear. We found that deficiency in the ubiquitin ligase Itch led to spontaneous colitis and increased susceptibility to colon cancer. Itch deficiency in the TH17 subset of helper T cells, innate lymphoid cells and γδ T cells resulted in the production of elevated amounts of IL-17 in the colonic mucosa. Mechanistically, Itch bound to the transcription factor ROR-γt and targeted ROR-γt for ubiquitination. Inhibition or genetic inactivation of ROR-γt attenuated IL-17 expression and reduced spontaneous colonic inflammation in Itch(-/-) mice. Thus, we have identified a previously unknown role for Itch in regulating IL-17-mediated colonic inflammation and carcinogenesis.

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Section: Discussionmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Itch Targets Ror-gt For Ubiquitinationmentioning

confidence: 99%

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Itch inhibits IL-17-mediated colon inflammation and tumorigenesis by ROR-γt ubiquitination

et al. 2016

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“…HECT E3 ligases are involved in numerous cellular processes, from UBE3C promoting growth and metastasis of renal cell carcinoma, to Nedd4 enhancing cell proliferation and autophagy, to Itch inhibiting skin inflammation (42)(43)(44). Reported diseaselinked mutations in UBE3B associated with the most severe forms of KOS include the seven different nonsense, frameshift, and splice site mutations that likely cause protein truncation before or at the beginning of the HECT domain and therefore are predicted to abolish UBE3B's ligase activity (24 -27).…”

Section: Discussionmentioning

confidence: 99%

UBE3B Is a Calmodulin-regulated, Mitochondrion-associated E3 Ubiquitin Ligase

Braganza

Zeng

et al. 2017

Journal of Biological Chemistry

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Recent genome-wide studies found that patients with hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels suffer from Kaufman oculocerebrofacial syndrome (KOS, also reported as blepharophimosis-ptosis-intellectual disability syndrome). The primary cause of KOS is autosomal recessive mutations in the gene UBE3B. However, to date, there are no studies that have determined the cellular or enzymatic function of UBE3B. Here, we report that UBE3B is a mitochondrion-associated protein with homologous to the E6-AP C terminus (HECT) E3 ubiquitin ligase activity. Mutating the catalytic cysteine (C1036A) or deleting the entire HECT domain (amino acids 758 -1068) results in loss of UBE3B's ubiquitylation activity. Knockdown of UBE3B in human cells induces changes in mitochondrial morphology and physiology, a decrease in mitochondrial volume, and a severe suppression of cellular proliferation. We also discovered that UBE3B interacts with calmodulin via its N-terminal isoleucine-glutamine (IQ) motif. Deletion of the IQ motif (amino acids 29 -58) results in loss of calmodulin binding and a significant increase in the in vitro ubiquitylation activity of UBE3B. In addition, we found that changes in calcium levels in vitro disrupt the calmodulin-UBE3B interaction. These studies demonstrate that UBE3B is an E3 ubiquitin ligase and reveal that the enzyme is regulated by calmodulin. Furthermore, the modulation of UBE3B via calmodulin and calcium implicates a role for calcium signaling in mitochondrial protein ubiquitylation, protein turnover, and disease.Ubiquitylation is a reversible post-translational modification that impacts most cellular processes. However, it is best known for targeting proteins for degradation by the 26S proteasome, and the ubiquitin/proteasome system (UPS) 2 is a major part of the cellular protein quality control network (1-5). Substrate modification can occur either by the attachment of a single ubiquitin molecule or a polyubiquitin chain, where one ubiquitin is conjugated to the next via an isopeptide bond (6). Conjugation of ubiquitin to one or more lysine residues on the substrate protein is mediated by the sequential action of a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3). Although there is limited diversity in E1 and E2 enzymes, numerous cellular E3 ligases specify the timing and substrate selection of ubiquitylation reactions.E3 ligases are mainly composed of three major families, the really interesting new gene (RING) family, the homologous to the E6-AP C terminus (HECT) family, and the RING-between-RING (RBR) family. The RING ligases catalyze the direct transfer of ubiquitin from the E2 to the substrate (7,8). Conversely, the HECT and RBR E3 ligases covalently transfer the ubiquitin from the E2 to a resident catalytic cysteine. This catalytic cysteine in the E3 ligase active site can then serve as the site of attachment for a thioester-linked polyubiqu...

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Itch attenuates CD4 T‐cell proliferation in mice by limiting WBP2 protein stability

et al. 2020

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To mount an antipathogen response, CD4 T cells must undergo rapid cell proliferation; however, poorly controlled expansion can result in diseases such as autoimmunity. One important regulator of T-cell activity is the E3 ubiquitin ligase Itch. Itch deficient patients suffer from extensive autoinflammation. Similarly, Itch deficient mice exhibit inflammation characterized by high numbers of activated CD4 T cells. While the role of Itch in limiting CD4 T-cell cytokine production has been extensively studied, it is less clear whether and how Itch regulates proliferation of these cells. We determined that Itch deficient CD4 T cells are hyperproliferative in vitro and in vivo, due to increased S phase entry. Whole cell proteomics analysis of Itch deficient primary mouse CD4 T cells revealed increased abundance of the β-catenin coactivator WW domain-binding protein 2 (WBP2). Furthermore, Itch deficient cells demonstrate increased WBP2 protein stability, and Itch and WBP2 interact in CD4 T cells. Knockdown of WBP2 in CD4 T cells caused reduced proliferation. Together, our data support that Itch attenuates CD4 T cell proliferation by promoting WBP2 degradation. This study identifies novel roles for Itch and WBP2 in regulating CD4 T cell proliferation, providing insight into how Itch may prevent inflammation.

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The E3 ubiquitin ligase Itch inhibits p38α signaling and skin inflammation through the ubiquitylation of Tab1

Cited by 39 publications

References 65 publications

Itch inhibits IL-17-mediated colon inflammation and tumorigenesis by ROR-γt ubiquitination

Itch inhibits IL-17-mediated colon inflammation and tumorigenesis by ROR-γt ubiquitination

UBE3B Is a Calmodulin-regulated, Mitochondrion-associated E3 Ubiquitin Ligase

Itch attenuates CD4 T‐cell proliferation in mice by limiting WBP2 protein stability

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