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

Kathania, Mahesh; Khare, Prashant; Zeng, Minghui; Cantarel, Brandi L.; Zhang, Haiying; Ueno, Hideki; Venuprasad, K.

doi:10.1038/ni.3488

Cited by 106 publications

(109 citation statements)

References 48 publications

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“…Recently published work found that Itch ubiquitylates RORγT, targeting it for degradation and helping to limit the abundance of Th17 cells in the colon30. We found that Ndfip1 also controls RORγT levels.…”

Section: Discussionsupporting

confidence: 50%

“…Of these cytokines, increased amounts of IL-17A and TNFα are known to promote colorectal cancer while the role of GM-CSF in colorectal cancer remains unclear5354. Our data suggests that the observed remarkable susceptibility of Itch-deficient mice to colitis and colorectal cancer30 is not only because of the quantity of Th17 cells found in the colon, but also because of the pathogenic potential of these Th17 cells.…”

Section: Discussionmentioning

confidence: 78%

“…Since Ndfip1-deficient Th17 cells produce higher amounts of IL-17A and GM-CSF upon restimulation, we hypothesized that Ndfip1-deficient cells might fail to degrade RORγT. Supporting this, it was recently shown that Itch ubiquitylates and degrades RORγT30. Given that Ndfip1 can help to activate Itch in T cells24, we tested whether in the absence of Ndfip1, RORγT fails to be degraded.…”

Section: Resultsmentioning

confidence: 98%

“…Loss of Itch results in a spontaneous, auto-inflammatory, Th2-predominant disease, similar to that seen in Ndfip1-deficient animals41, albeit with a delayed onset. Recently it was shown that mice lacking Itch have hyper-functional Th17 cells30. To investigate whether Itch, like Ndfip1, is required for the regulation of Th17 cell numbers and cytokine production, we generated Itch IL-4 DKO animals and examined Th17 cells in their lungs.…”

Section: Resultsmentioning

confidence: 99%

“…However, it is unknown whether Ndfip1 has direct roles within Th17s. Very recently, the catalytic E3 ligase, Itch, was shown to ubiquitylate RORγT, driving its degradation and helping to limit the generation of Th17 cells in the colon30. However, it remains unclear how the increased levels of RORγT that occur in the absence of Itch impact Th17 cell function.…”

mentioning

confidence: 99%

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Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production

Layman¹,

Sprout²,

Phillips³

et al. 2017

Sci Rep

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While Th17 cells can protect against colonization by pathogenic organisms, they also have the potential to become pathogenic and promote autoimmune and inflammatory diseases. Mechanisms that control their pathogenic potential remain poorly understood. Here we show that Ndfip1, a co-activator of the E3 ubiquitin ligase Itch, restricts the frequency and pathogenicity of Th17 cells. Mice lacking Ndfip1 have increased numbers of Th17 cells, and this increase is cell intrinsic. We found that Ndfip1 restricts production of the proinflammatory cytokines in Th17 cells. Increased cytokine production correlated with reduced degradation and accumulation of RORγT. When transferred in vivo, Th17 cells lacking Ndfip1 were more likely to maintain their ability to make IL-17, were more potent proinflammatory cytokine producers, and were powerful inducers of colitis. Together our data support an essential role for Ndfip1 in degrading RORγT and suppressing Th17 lineage stability, proinflammatory cytokine production, and pathogenicity.

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Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production

Layman¹,

Sprout²,

Phillips³

et al. 2017

Sci Rep

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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 deficiency promotes antigen‐driven B‐cell responses in mice

Fang

Zhai

et al. 2020

Eur J Immunol

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Deficiency of Itch, an E3 ubiquitin ligase, usually induced severe systemic and progressive autoimmune disease. The Itch function is well studied in T cells but not in B cells. We hypothesize that B‐cell‐specific Itch deficiency promoted antigen‐induced B‐cell activation and antibody‐expressing plasma cell (PC) production. We found that unlike Itch KO, Itch cKO (CD19creItchf/f) mice did not demonstrated a significant increase in the sizes of spleens and LNs, antibody level, and base mutation of antibody gene. However, in line with the fact that Itch expression decreased in GC B cells, PCs, and plasmablast (PB)‐like SP 2/0 cells, Itch deficiency promoted B‐cell activation and antibody production induced by antigens including lipopolysaccharide (LPS) and sheep red blood cells (SRBCs). Mechanistically, we found that Itch deficiency promotes antigen‐induced cytokine production because Itch controls the proteins (e.g., eIF3a, eIF3c, eIF3h) with translation initiation factor activity. Altogether, our data suggest that Itch deficiency promotes antigen‐driven B‐cell response. This may provide hints for Itch‐targeted treatment of patients with autoimmune disease.

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

Cited by 106 publications

References 48 publications

Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production

Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production

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

The E3 ubiquitin ligase Itch deficiency promotes antigen‐driven B‐cell responses in mice

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