Nur77 prevents excessive osteoclastogenesis by inducing ubiquitin ligase Cbl-b to mediate NFATc1 self-limitation

  1. Xiaoxiao Li
  2. Wei Wei
  3. HoangDinh Huynh
  4. Hao Zuo
  5. Xueqian Wang
  6. Yihong Wan  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States

Abstract

Osteoclasts are bone-resorbing cells essential for skeletal remodeling. However, over-active osteoclasts can cause bone degenerative disorders. Therefore, the level of NFATc1, the master transcription factor of osteoclast, must be tightly controlled. Although the activation and amplification of NFATc1 have been extensively studied, how NFATc1 signaling is eventually resolved is unclear. Here, we uncover a novel and critical role of the orphan nuclear receptor Nur77 in mediating an NFATc1 self-limiting regulatory loop to prevent excessive osteoclastogenesis. Nur77 deletion leads to low bone mass owing to augmented osteoclast differentiation and bone resorption. Mechanistically, NFATc1 induces Nur77 expression at late stage of osteoclast differentiation; in turn, Nur77 transcriptionally up-regulates E3 ubiquitin ligase Cbl-b, which triggers NFATc1 protein degradation. These findings not only identify Nur77 as a key player in osteoprotection and a new therapeutic target for bone diseases, but also elucidate a previously unrecognized NFATc1→Nur77→Cblb⎯•NFATc1 feedback mechanism that confers NFATc1 signaling autoresolution.

Article and author information

Author details

  1. Xiaoxiao Li

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Wei Wei

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. HoangDinh Huynh

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Hao Zuo

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Xueqian Wang

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yihong Wan

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    yihong.wan@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All protocols for mouse experiments were approved under number 2008-0324 by the Institutional Animal Care and Use Committee of UTSW.

Copyright

© 2015, Li et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,761
    views
  • 392
    downloads
  • 24
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Xiaoxiao Li
  2. Wei Wei
  3. HoangDinh Huynh
  4. Hao Zuo
  5. Xueqian Wang
  6. Yihong Wan
(2015)
Nur77 prevents excessive osteoclastogenesis by inducing ubiquitin ligase Cbl-b to mediate NFATc1 self-limitation
eLife 4:e07217.
https://doi.org/10.7554/eLife.07217

Share this article

https://doi.org/10.7554/eLife.07217

Further reading

    1. Cell Biology
    Mitsuhiro Abe, Masataka Yanagawa ... Yasushi Sako
    Research Article

    Anionic lipid molecules, including phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), are implicated in the regulation of epidermal growth factor receptor (EGFR). However, the role of the spatiotemporal dynamics of PI(4,5)P2 in the regulation of EGFR activity in living cells is not fully understood, as it is difficult to visualize the local lipid domains around EGFR. Here, we visualized both EGFR and PI(4,5)P2 nanodomains in the plasma membrane of HeLa cells using super-resolution single-molecule microscopy. The EGFR and PI(4,5)P2 nanodomains aggregated before stimulation with epidermal growth factor (EGF) through transient visits of EGFR to the PI(4,5)P2 nanodomains. The degree of coaggregation decreased after EGF stimulation and depended on phospholipase Cγ, the EGFR effector hydrolyzing PI(4,5)P2. Artificial reduction in the PI(4,5)P2 content of the plasma membrane reduced both the dimerization and autophosphorylation of EGFR after stimulation with EGF. Inhibition of PI(4,5)P2 hydrolysis after EGF stimulation decreased phosphorylation of EGFR-Thr654. Thus, EGFR kinase activity and the density of PI(4,5)P2 around EGFR molecules were found to be mutually regulated.

    1. Cell Biology
    Wonjo Jang, Kanishka Senarath ... Nevin A Lambert
    Tools and Resources

    Classical G-protein-coupled receptor (GPCR) signaling takes place in response to extracellular stimuli and involves receptors and heterotrimeric G proteins located at the plasma membrane. It has recently been established that GPCR signaling can also take place from intracellular membrane compartments, including endosomes that contain internalized receptors and ligands. While the mechanisms of GPCR endocytosis are well understood, it is not clear how well internalized receptors are supplied with G proteins. To address this gap, we use gene editing, confocal microscopy, and bioluminescence resonance energy transfer to study the distribution and trafficking of endogenous G proteins. We show here that constitutive endocytosis is sufficient to supply newly internalized endocytic vesicles with 20–30% of the G protein density found at the plasma membrane. We find that G proteins are present on early, late, and recycling endosomes, are abundant on lysosomes, but are virtually undetectable on the endoplasmic reticulum, mitochondria, and the medial-trans Golgi apparatus. Receptor activation does not change heterotrimer abundance on endosomes. Our findings provide a subcellular map of endogenous G protein distribution, suggest that G proteins may be partially excluded from nascent endocytic vesicles, and are likely to have implications for GPCR signaling from endosomes and other intracellular compartments.