title: JMJD5, a Jumonji C (JmjC) domain-containing protein, negatively regulates osteoclastogenesis by facilitating NFATc1 protein degradation.
abstract: Osteoclastogenesis is a highly regulated process governed by diverse classes of regulators. Among them, nuclear factor of activated T-cells calcineurin-dependent 1 (NFATc1) is the primary osteoclastogenic transcription factor, and its expression is transcriptionally induced during early osteoclastogenesis by receptor activation of nuclear factor κB ligand (RANKL), an osteoclastogenic cytokine. Here, we report the novel enzymatic function of JMJD5, which regulates NFATc1 protein stability. Among the tested Jumonji C (JmjC) domain-containing proteins, decreased mRNA expression levels during osteoclastogenesis were found for JMJD5 in RAW264 cells stimulated by RANKL. To examine the functional role of JMJD5 in osteoclast differentiation, we established stable JMJD5 knockdown cells, and osteoclast formation was assessed. Down-regulated expression of JMJD5 led to accelerated osteoclast formation together with induction of several osteoclast-specific genes such as Ctsk and DC-STAMP, suggesting that JMJD5 is a negative regulator in osteoclast differentiation. Although JMJD5 was recently reported as a histone demethylase for histone H3K36me2, no histone demethylase activity was detected in JMJD5 in vitro or in living cells, even for other methylated histone residues. Instead, JMJD5 co-repressed transcriptional activity by destabilizing NFATc1 protein. Protein hydroxylase activity mediated by the JmjC domain in JMJD5 was required for the observed functions of JMJD5. JMJD5 induced the association of hydroxylated NFATc1 with the E3 ubiquitin ligase Von Hippel-Lindau tumor suppressor (VHL), thereby presumably facilitating proteasomal degradation of NFATc1 via ubiquitination. Taken together, the present study demonstrated that JMJD5 is a post-translational co-repressor for NFATc1 that attenuates osteoclastogenesis.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Youn
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yokoyama
authors.forename: Sally
authors.initials: S
authors.lastname: Fujiyama-Nakamura
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ohtake
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Minehata
authors.forename: Hisataka
authors.initials: H
authors.lastname: Yasuda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Imai
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D044127:Epigenesis, Genetic / Q000502:physiology; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation / Q000502:physiology; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D025801:Ubiquitin; D056466:Histone Demethylases; C550342:KDM8 protein, human; D046988:Proteasome Endopeptidase Complex