Wu, XiaomianFukushima, HidefumiNorth, BrianNagaoka, YoshiyukiNagashima, KatsuyukiDeng, FengOkabe, KojiInuzuka, HiroyukiWei, Wenyi2014-09-082014Wu, Xiaomian, Hidefumi Fukushima, Brian J. North, Yoshiyuki Nagaoka, Katsuyuki Nagashima, Feng Deng, Koji Okabe, Hiroyuki Inuzuka, and Wenyi Wei. 2014. “SCFβ-TRCP regulates osteoclastogenesis via promoting CYLD ubiquitination.” Oncotarget 5 (12): 4211-4221.1949-2553http://nrs.harvard.edu/urn-3:HUL.InstRepos:12785930CYLD 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.en-USβ-TRCPCYLDtumor suppressordegradationphosphorylationubiquitinationJournal Article2014-09-0810.18632/oncotarget.1971