Ndfip1 Regulates Itch Ligase Activity and Airway Inflammation via UbcH7

Kathania, Mahesh; Zeng, Minghui; Yadav, Viveka Nand; Moghaddam, Seyed Javad; Yang, Baoli; Venuprasad, K.

doi:10.4049/jimmunol.1402742

Cited by 11 publications

(10 citation statements)

References 41 publications

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“…This study focused predominantly on Ndfip1, an activator of Itch catalytic activity24284849. It has been shown that the loss of Ndfip1 globally, or following conditional deletion in T cells, causes spontaneous autoinflammatory disease that is associated with high numbers of activated CD4 T cells, increased numbers of Th1, Th2, and Th17 cells, and premature death24262729.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…This function of Itch appears to have in vivo relevance. Itch‐deficient mice showed increased transcriptional levels of IL‐6, TNFα, and IL‐1β in the lungs after stimulation with inactive Haemophilus Influenzae ( H. flu ) and this phenomenon was attributed to increased Tak1 activity in the absence of Itch 70 …”

Section: Itch In Innate Cell Functionmentioning

confidence: 99%

Itch regulation of innate and adaptive immune responses in mice and humans

Field

Moser

Oliver

2020

Journal of Leukocyte Biology

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The E3 ubiquitin ligase Itch has long been appreciated to be a critical suppressor of inflammation, first identified as a regulator of Th2 differentiation and lung inflammation. Recent studies have revealed novel roles for this protein in mouse and human disease, and it is now clear that Itch also limits the function of other lymphocytes, innate immune cells, and nonhematopoietic cells to regulate immunity. In addition to Th2 cells, Itch also regulates Th17 and regulatory T cells. Itch regulates humoral immunity through direct roles in T follicular helper cells and T follicular regulatory cells, and B cells. Furthermore, Itch limits innate immune responses, such as macrophage cytokine production. Through these cell‐intrinsic functions, Itch regulates the interplay between innate and adaptive immune cells, resulting in profound autoinflammation in Itch‐deficient mice. Whereas Itch deficiency was previously thought to be an extremely rare occurrence humans, whole exome sequencing of patients with unexplained autoimmune disease has revealed at least two additional cases of Itch deficiency in the last year alone, each caused by distinct mutations within the Itch gene. The recent identification of these patients suggests that Itch mutations may be more common than previously thought, and demonstrates the need to understand how this protein regulates inflammation and autoimmune disease.

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“…In addition to TNFα-induced NFκB activation, Itch inhibited NFκB responses to pattern recognition receptor ligands. Itch-dependent degradation of Rip2 or Tak1 could limit NFκB activation after BMDM exposure to Haemophilus influenza and the microbial ligand muramyl dipeptide (MDP), respectively [16,108]. Although loss of Itch in innate cells is insufficient to initiate spontaneous autoimmunity, these studies suggest that Itch helps to dampen inflammatory responses that likely drive tissue destruction and exacerbate disease after the onset of autoimmunity.…”

Section: Itch Regulates Immune Cell Function To Prevent Autoimmune DImentioning

confidence: 99%

“…Mechanistically, PY motifs within Ndfip1 interacted with Itch WW domains to relieve intramolecular autoinhibition, allowing the catalytic HECT domain to transfer ubiquitin to JunB [13,119]. Ndfip1 also was required for Itch-dependent degradation of RORγt to prevent Th17 differentiation [103] and Ndfip1 in macrophages was shown to activate Itch-dependent degradation of Tak1 to dampen NFκB signaling [108]. Recently, the Ndfip1 homolog, Ndfip2, has also been found to activate Itch.…”

Section: Molecular Regulation Of Itch Enzymatic Activitymentioning

confidence: 99%

Regulation of autoimmune disease by the E3 ubiquitin ligase Itch

Moser

Oliver

2019

Cellular Immunology

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Itch is a HECT type E3 ubiquitin ligase that is required to prevent the development of autoimmune disease in both mice and humans. Itch is expressed in most mammalian cell types, and, based on published data, it regulates many cellular pathways ranging from T cell differentiation to liver tumorigenesis. Since 1998, when Itch was first discovered, hundreds of publications have described mechanisms through which Itch controls various biologic activities in both immune and non-immune cells. Other studies have provided insight into how Itch catalytic activity is regulated. However, while autoimmunity is the primary clinical feature that occurs in both mice and humans lacking Itch, and Itch control of immune cell function has been well-studied, it remains unclear how Itch prevents the emergence of autoimmune disease. In this review, we explore recent discoveries that advance our understanding of how Itch regulates immune cell biology, and the extent to which these clarify how Itch prevents autoimmune disease. Additionally, we discuss how molecular regulators of Itch impact its ability to control these processes, as this may provide clues on how to therapeutically target Itch to treat patients with autoimmune disease.

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Ndfip1 Regulates Itch Ligase Activity and Airway Inflammation via UbcH7

Cited by 11 publications

References 41 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 regulation of innate and adaptive immune responses in mice and humans

Regulation of autoimmune disease by the E3 ubiquitin ligase Itch

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