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.
Highlights
FK506 binding proteins (FKBPs) are multifunctional proteins highly conserved across the species and abundantly expressed in the cell
FKBP51 has been shown to inhibit apoptosis in melanoma cells [10,11,12]. In agreement with these previous reports, we found that FKBP51 knockdown promoted TNF␣-stimulated expression of the proapoptotic factor Bax, at both protein (Figure 1c, upper) and mRNA (Figure 1c, lower) levels
The effect of FKBP51 knockdown on IKK activity was not limited to A375 cells, since similar results were obtained with another melanoma cell line, SAN
Summary
FK506 binding proteins (FKBPs) are multifunctional proteins highly conserved across the species and abundantly expressed in the cell. In addition to a well-established role in immunosuppression, immunophilins modulate several signal transduction pathways in the cell, due to their isomerase activity and the capability to interact with other proteins, inducing changes in conformation and function of partner proteins [2,3]. FKBP51, encoded by the FKBP5 gene, has a C-terminal tetratricopeptide repeat (TPR) domain, known to be involved in interaction with Hsp as well as other proteins [4,5]. This structural feature suggests that FKBP51 may share some functions with heat shock proteins [6]. The FK1 domain is capable of PPIase activity and immunosuppressant drug binding, while the FK2 domain seems to have a structural role [5,6]
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