KBTBD11, a Novel BTB-Kelch Protein, is a Negative Regulator of Osteoclastogenesis Through Controlling Cullin3-mediated Ubiquitination of NFATc1

Overview

Journal Sci Rep

Specialty Science

Date 2019 Mar 7

PMID 30837587

Citations 16

Authors

Shun Narahara

Eiko Sakai

Tomoko Kadowaki

Yu Yamaguchi

Haruna Narahara

Kuniaki Okamoto

Izumi Asahina

Takayuki Tsukuba

Affiliations

Soon will be listed here.

Abstract

Kelch repeat and BTB domain-containing protein 11 (KBTBD11) is a member of the KBTBD subfamily of proteins that possess a BTB domain and Kelch repeats. Despite the presence of the Kbtbd11 gene in mammalian genomes, there are few reports about KBTBD11 at present. In this study, we identified the novel protein KBTBD11 as a negative regulator of osteoclast differentiation. We found that expression of KBTBD11 increased during osteoclastogenesis. Small-interfering-RNA-mediated knockdown of KBTBD11 enhanced osteoclast formation, and markedly increased the expression of several osteoclast marker genes compared with control cells. Conversely, KBTBD11 overexpression impaired osteoclast differentiation, and decreased the expression of osteoclast marker genes. Among six major signaling pathways regulating osteoclast differentiation, KBTBD11 predominantly influenced the nuclear factor of activated T cell cytoplasmic-1 (NFATc1) pathway. Mechanistically, KBTBD11 was found to interact with an E3 ubiquitin ligase, Cullin3. Further experiments involving immunoprecipitation and treatment with MG132, a proteasome inhibitor, showed that the KBTBD11-Cullin3 promotes ubiquitination and degradation of NFATc1 by the proteasome. Considering that NFATc1 is an essential factor for osteoclast differentiation, the KBTBD11 and Cullin3 probably regulate the levels of NFATc1 through the ubiquitin-proteasome degradation system. Thus, KBTBD11 negatively modulates osteoclast differentiation by controlling Cullin3-mediated ubiquitination of NFATc1.

Citing Articles

Autophagy Regulator Rufy 4 Promotes Osteoclastic Bone Resorption by Orchestrating Cytoskeletal Organization via Its RUN Domain.

Sakai E, Saito M, Koyanagi Y, Takayama Y, Farhana F, Yamaguchi Y Cells. 2024; 13(21.

PMID: 39513873 PMC: 11545195. DOI: 10.3390/cells13211766.

Recent advances of NFATc1 in rheumatoid arthritis-related bone destruction: mechanisms and potential therapeutic targets.

Zheng H, Liu Y, Deng Y, Li Y, Liu S, Yang Y Mol Med. 2024; 30(1):20.

PMID: 38310228 PMC: 10838448. DOI: 10.1186/s10020-024-00788-w.

Essentiality of Nfatc1 short isoform in osteoclast differentiation and its self-regulation.

Omata Y, Tachibana H, Aizaki Y, Mimura T, Sato K Sci Rep. 2023; 13(1):18797.

PMID: 37914750 PMC: 10620225. DOI: 10.1038/s41598-023-45909-3.

The role of E3 ubiquitin ligases in bone homeostasis and related diseases.

Dong Y, Chen Y, Ma G, Cao H Acta Pharm Sin B. 2023; 13(10):3963-3987.

PMID: 37799379 PMC: 10547920. DOI: 10.1016/j.apsb.2023.06.016.

KBTBD11, encoding a novel PPARγ target gene, is involved in NFATc1 proteolysis by interacting with HSC70 and HSP60.

Watanabe K, Matsumoto A, Tsuda H, Iwamoto S Sci Rep. 2022; 12(1):20273.

PMID: 36434268 PMC: 9700792. DOI: 10.1038/s41598-022-24929-5.

References

Canning P, Cooper C, Krojer T, Murray J, Pike A, Chaikuad A . Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases. J Biol Chem. 2013; 288(11):7803-7814. PMC: 3597819. DOI: 10.1074/jbc.M112.437996. View

Boyle W, Simonet W, Lacey D . Osteoclast differentiation and activation. Nature. 2003; 423(6937):337-42. DOI: 10.1038/nature01658. View

Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H . Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002; 3(6):889-901. DOI: 10.1016/s1534-5807(02)00369-6. View

Purev E, Neff L, Horne W, Baron R . c-Cbl and Cbl-b act redundantly to protect osteoclasts from apoptosis and to displace HDAC6 from beta-tubulin, stabilizing microtubules and podosomes. Mol Biol Cell. 2009; 20(18):4021-30. PMC: 2743621. DOI: 10.1091/mbc.e09-03-0248. View

du Puy L, Beqqali A, van Tol H, Monshouwer-Kloots J, Passier R, Haagsman H . Sarcosin (Krp1) in skeletal muscle differentiation: gene expression profiling and knockdown experiments. Int J Dev Biol. 2012; 56(4):301-9. DOI: 10.1387/ijdb.113327lp. View

Yasui T, Hirose J, Aburatani H, Tanaka S . Epigenetic regulation of osteoclast differentiation. Ann N Y Acad Sci. 2011; 1240:7-13. DOI: 10.1111/j.1749-6632.2011.06245.x. View

Ernkvist M, Persson N, Audebert S, Lecine P, Sinha I, Liu M . The Amot/Patj/Syx signaling complex spatially controls RhoA GTPase activity in migrating endothelial cells. Blood. 2008; 113(1):244-53. PMC: 2614636. DOI: 10.1182/blood-2008-04-153874. View

Genschik P, Sumara I, Lechner E . The emerging family of CULLIN3-RING ubiquitin ligases (CRL3s): cellular functions and disease implications. EMBO J. 2013; 32(17):2307-20. PMC: 3770339. DOI: 10.1038/emboj.2013.173. View

Marini F, Cianferotti L, Brandi M . Epigenetic Mechanisms in Bone Biology and Osteoporosis: Can They Drive Therapeutic Choices?. Int J Mol Sci. 2016; 17(8). PMC: 5000726. DOI: 10.3390/ijms17081329. View

10.

Zhang H, Wu C, Matesic L, Li X, Wang Z, Boyce B . Ubiquitin E3 ligase Itch negatively regulates osteoclast formation by promoting deubiquitination of tumor necrosis factor (TNF) receptor-associated factor 6. J Biol Chem. 2013; 288(31):22359-68. PMC: 3829326. DOI: 10.1074/jbc.M112.442459. View

11.

Perez-Torrado R, Yamada D, Defossez P . Born to bind: the BTB protein-protein interaction domain. Bioessays. 2006; 28(12):1194-202. DOI: 10.1002/bies.20500. View

12.

Lee K, Kim M, Ahn H, Kim H, Shin H, Jeong D . Blocking of the Ubiquitin-Proteasome System Prevents Inflammation-Induced Bone Loss by Accelerating M-CSF Receptor c-Fms Degradation in Osteoclast Differentiation. Int J Mol Sci. 2017; 18(10). PMC: 5666736. DOI: 10.3390/ijms18102054. View

13.

Stogios P, Prive G . The BACK domain in BTB-kelch proteins. Trends Biochem Sci. 2004; 29(12):634-7. DOI: 10.1016/j.tibs.2004.10.003. View

14.

Gupta V, Ravenscroft G, Shaheen R, Todd E, Swanson L, Shiina M . Identification of KLHL41 Mutations Implicates BTB-Kelch-Mediated Ubiquitination as an Alternate Pathway to Myofibrillar Disruption in Nemaline Myopathy. Am J Hum Genet. 2013; 93(6):1108-17. PMC: 3852928. DOI: 10.1016/j.ajhg.2013.10.020. View

15.

Matsumoto M, Sudo T, Saito T, Osada H, Tsujimoto M . Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand (RANKL). J Biol Chem. 2000; 275(40):31155-61. DOI: 10.1074/jbc.M001229200. View

16.

Darnay B, Ni J, Moore P, Aggarwal B . Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif. J Biol Chem. 1999; 274(12):7724-31. DOI: 10.1074/jbc.274.12.7724. View

17.

Paxton C, Cosgrove R, Drozd A, Wiggins E, Woodhouse S, Watson R . BTB-Kelch protein Krp1 regulates proliferation and differentiation of myoblasts. Am J Physiol Cell Physiol. 2011; 300(6):C1345-55. PMC: 3118629. DOI: 10.1152/ajpcell.00321.2010. View

18.

Sambuughin N, Swietnicki W, Techtmann S, Matrosova V, Wallace T, Goldfarb L . KBTBD13 interacts with Cullin 3 to form a functional ubiquitin ligase. Biochem Biophys Res Commun. 2012; 421(4):743-9. PMC: 5148137. DOI: 10.1016/j.bbrc.2012.04.074. View

19.

Bowlin K, Embree L, Garry M, Garry D, Shi X . Kbtbd5 is regulated by MyoD and restricted to the myogenic lineage. Differentiation. 2013; 86(4-5):184-91. DOI: 10.1016/j.diff.2013.08.002. View

20.

Ravenscroft G, Miyatake S, Lehtokari V, Todd E, Vornanen P, Yau K . Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy. Am J Hum Genet. 2013; 93(1):6-18. PMC: 3710748. DOI: 10.1016/j.ajhg.2013.05.004. View