Work

SCFβ-TRCP regulates osteoclastogenesis via promoting CYLD ubiquitination

Year: 2014

Type: article

Abstract: // Xiaomian Wu 1,2,* , Hidefumi Fukushima 2,3,* , Brian J. North 2 , Yoshiyuki Nagaoka 3 , Katsuyuki Nagashima 3 , Feng Deng 1 , Koji Okabe 3 , Hiroyuki Inuzuka 2 and Wenyi Wei 2 1 Chongqing key Laboratory for Oral Diseases and Biomedical Sciences, The Affiliated Hospital of Stomatology, Chongqing Medical University, Chongqing, P.R. China 2 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 3 Department of Physiological Sciences and Molecular Biology, Fukuoka Dental College, Fukuoka, Japan * These authors contributed equally to this work Correspondence: Hiroyuki Inuzuka, email: // Wenyi Wei, email: // Keywords : β-TRCP, CYLD, tumor suppressor, degradation, phosphorylation, ubiquitination Received : April 1, 2014 Accepted : May 12, 2014 Published : May 14, 2014 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 SCF β-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.

Source: Oncotarget

DOI: 10.18632/oncotarget.1971