title: FKBP51 employs both scaffold and isomerase functions to promote NF-κB activation in melanoma.
abstract: Melanoma is the most aggressive skin cancer; its prognosis, particularly in advanced stages, is disappointing largely due to the resistance to conventional anticancer treatments and high metastatic potential. NF-κB constitutive activation is a major factor for the apoptosis resistance of melanoma. Several studies suggest a role for the immunophilin FKBP51 in NF-κB activation, but the underlying mechanism is still unknown. In the present study, we demonstrate that FKBP51 physically interacts with IKK subunits, and facilitates IKK complex assembly. FKBP51-knockdown inhibits the binding of IKKγ to the IKK catalytic subunits, IKK-α and -β, and attenuates the IKK catalytic activity. Using FK506, an inhibitor of the FKBP51 isomerase activity, we found that the IKK-regulatory role of FKBP51 involves both its scaffold function and its isomerase activity. Moreover, FKBP51 also interacts with TRAF2, an upstream mediator of IKK activation. Interestingly, both FKBP51 TPR and PPIase domains are required for its interaction with TRAF2 and IKKγ, whereas only the TPR domain is involved in interactions with IKKα and β. Collectively, these results suggest that FKBP51 promotes NF-κB activation by serving as an IKK scaffold as well as an isomerase. Our findings have profound implications for designing novel melanoma therapies based on modulation of FKBP51.
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples 80131, Italy Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Simona
authors.initials: S
authors.lastname: Romano
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
authors.forename: Yichuan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mako
authors.initials: M
authors.lastname: Nakaya
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples 80131, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: D'Angelillo
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mikyoung
authors.initials: M
authors.lastname: Chang
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department Translational Research in Psychiatry, Max Planck Institute of Psychiatry, München 80804, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Hausch
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples 80131, Italy Department of Movement Sciences and Wellness, University of Naples 'Parthenope', Naples 80133, Italy.
authors.forename: Mariorosario
authors.initials: M
authors.lastname: Masullo
authors.affiliation: Department Translational Research in Psychiatry, Max Planck Institute of Psychiatry, München 80804, Germany.
authors.forename: Xixi
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples 80131, Italy mariafiammetta.romano@unina.it.
authors.forename: Maria Fiammetta
authors.initials: MF
authors.lastname: Romano
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D051550:I-kappa B Kinase; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5