title: SCFβ-TRCP regulates osteoclastogenesis via promoting CYLD ubiquitination.
abstract: CYLD negatively regulates the NF-κB signaling pathway and osteoclast differentiation largely through antagonizing TNF receptor-associated factor (TRAF)-mediated K63-linkage polyubiquitination in osteoclast precursor cells. CYLD activity is controlled by IκB kinase (IKK), but the molecular mechanism(s) governing CYLD protein stability remains largely undefined. Here, we report that SCFβ-TRCP regulates the ubiquitination and degradation of CYLD, a process dependent on prior phosphorylation of CYLD at Ser432/Ser436 by IKK. Furthermore, depletion of β-TRCP induced CYLD accumulation and TRAF6 deubiquitination in osteoclast precursor cells, leading to suppression of RANKL-induced osteoclast differentiation. Therefore, these data pinpoint the IKK/β-TRCP/CYLD signaling pathway as an important modulator of osteoclastogenesis.
authors: Chongqing key Laboratory for Oral Diseases and Biomedical Sciences, The Affiliated Hospital of Stomatology, Chongqing Medical University, Chongqing, P.R. China; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors: Xiaomian
authors: X
authors: Wu
authors: Hidefumi
authors: H
authors: Fukushima
authors: Brian J
authors: BJ
authors: North
authors: Yoshiyuki
authors: Y
authors: Nagaoka
authors: Katsuyuki
authors: K
authors: Nagashima
authors: Feng
authors: F
authors: Deng
authors: Koji
authors: K
authors: Okabe
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors: Hiroyuki
authors: H
authors: Inuzuka
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors: Wenyi
authors: W
authors: Wei
mesh_terms: D000818:Animals; D000074749:Deubiquitinating Enzyme CYLD; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D010010:Osteoclasts; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D025521:Tumor Suppressor Proteins; D044843:SKP Cullin F-Box Protein Ligases; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD