Involvement of kinase PKC-zeta in the p62/p62^P392L-driven activation of NF-¦ÊB in human osteoclasts

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• 作者：Estelle Chamoux ; Stephen McManus ; Gino Laberge ; Martine Bisson ; Sophie Roux ; ^{Sophie.Roux@USherbrooke.ca}
• 关键词：OC ; osteoclast ; PDB ; Paget's disease of bone ; RANKL ; receptor activator of NF-¦ÊB ligand ; UBA ; ubiquitin-associated domain ; PKC¦Æ ; protein kinase C zeta ; PDK1 ; 3-phosphoinositide-dependent protein kinase 1 ; I¦ÊB ; inhibitor of NF-¦ÊB ; IKK ; I¦ÊB kinase
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：2013
• 出版时间：March, 2013
• 年：2013
• 卷：1832
• 期：3
• 页码：475-484
• 全文大小：1516 K

文摘

Mutations of the gene encoding sequestosome1 (SQSTM1/p62), clustering in or near the UBA domain, have been described in Paget's disease of bone (PDB); among these the P392L substitution is the most prevalent. Protein p62 mediates several cell functions, including the control of NF-¦ÊB signaling, and autophagy. This scaffolding protein interacts with atypical PKC¦Æ in the RANKL-induced signaling complex. We have previously shown that osteoclasts (OCs) overexpressing the p62^P392L variant were in a constitutively activated state, presenting activated kinase p-PKC¦Æ/¦Ë and activated NF-¦ÊB prior to RANKL stimulation. In the present study, we investigated the relationships between PKC¦Æ and NF-¦ÊB activation in human OCs transfected with p62 variants. We showed that PKC¦Æ and p-PKC¦Æ/¦Ë co-localize with p62, and that PKC¦Æ is involved in the RANKL-induced NF-¦ÊB activation and in the RANKL-independent activation of NF-¦ÊB observed in p62^P392L-transfected cells. We also observed a basal and RANKL-induced increase in I¦ÊB¦Á levels in the presence of the p62^P392L mutation that contrasted with the NF-¦ÊB activation. In this study we propose that PKC¦Æ plays a role in the activation of NF-¦ÊB by acting as a p65 (RelA) kinase at Ser⁵³⁶, independently of I¦ÊB¦Á; this alternative pathway could be used preferentially in the presence of the p62^P392L mutation, which may hinder the ubiquitin-proteasome pathway. Overall, our results highlight the importance of p62-associated PKC¦Æ in the overactive state of pagetic OCs and in the activation of NF-¦ÊB, particularly in the presence of the p62^P392L mutation.