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

Xiaoxiao Li, Wei Wei, Hoangdinh Huynh, Hao Zuo, Xueqian Wang, Yihong Wan

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 andamplification of NFATc1 have been extensively studied, how NFATc1 signaling is eventually resolvedis unclear. Here, we uncover a novel and critical role of the orphan nuclear receptor Nur77 inmediating an NFATc1 self-limiting regulatory loop to prevent excessive osteoclastogenesis. Nur77deletion 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.

Original languageEnglish (US)
Article numbere07217
JournaleLife
Volume4
Issue numberJULY 2015
DOIs
StatePublished - Jul 14 2015

Fingerprint

Osteoclasts
Ligases
Ubiquitin
Osteogenesis
Bone
Bone and Bones
Nuclear Receptor Subfamily 4, Group A, Member 1
Ubiquitin-Protein Ligases
Bone Diseases
Bone Resorption
Proteolysis
Transcription Factors
Up-Regulation
Chemical activation
Feedback
Degradation
Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

Cite this

Nur77 prevents excessive osteoclastogenesis by inducing ubiquitin ligase Cbl-b to mediate NFATc1 self-limitation. / Li, Xiaoxiao; Wei, Wei; Huynh, Hoangdinh; Zuo, Hao; Wang, Xueqian; Wan, Yihong.

In: eLife, Vol. 4, No. JULY 2015, e07217, 14.07.2015.

Research output: Contribution to journalArticle

Li, Xiaoxiao ; Wei, Wei ; Huynh, Hoangdinh ; Zuo, Hao ; Wang, Xueqian ; Wan, Yihong. / Nur77 prevents excessive osteoclastogenesis by inducing ubiquitin ligase Cbl-b to mediate NFATc1 self-limitation. In: eLife. 2015 ; Vol. 4, No. JULY 2015.
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