Chen, G., Cao, P. & Goeddel, D. V. TNF-induced recruitment and activation of the IkK complex require Cdc37 and Hsp90. Mol. Cell 9, 401-410

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Molecular Cell (Impact Factor: 14.02). 03/2002; 9(2):401-10. DOI: 10.1016/S1097-2765(02)00450-1
Source: PubMed


The IKK complex, containing two catalytic subunits IKKalpha and IKKbeta and a regulatory subunit NEMO, plays central roles in signal-dependent activation of NF-kappaB. We identify Cdc37 and Hsp90 as two additional components of the IKK complex. IKKalpha/IKKbeta/NEMO and Cdc37/Hsp90 form an approximately 900 kDa heterocomplex, which is assembled via direct interactions of Cdc37 with Hsp90 and with the kinase domain of IKKalpha/IKKbeta. Geldanamycin (GA), an antitumor agent that disrupts the formation of this heterocomplex, prevents TNF-induced activation of IKK and NF-kappaB. GA treatment reduces the size of the IKK complex and abolishes TNF-dependent recruitment of the IKK complex to TNF receptor 1 (TNF-R1). Therefore, heterocomplex formation with Cdc37/Hsp90 is a prerequisite for TNF-induced activation and trafficking of IKK from the cytoplasm to the membrane.


Available from: Dave Goeddel, Jul 10, 2014
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    • "Hsp90 is an abundant, highly conserved cellular chaperone that functions as a key component of a multiprotein chaperone complex, which includes Cdc37 and several other proteins that regulate folding, maturation, stabilization, and renaturation of a select group of target proteins [8], [9]. It has been shown that Hsp90 interacts with IκB kinases and signaling proteins of the nuclear factor-κB (NF-κB) pathway, including MEKK3, NIK, RIP1, TAK1, and TBK1 [10]–[14], and Hsp90-Cdc37 serves as a transiently acting essential regulatory component of the IκB kinase (IKK) signaling [15]. "
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    ABSTRACT: Nuclear factor-κB (NF-κB) plays a central role in the regulation of diverse biological processes, including immune responses, development, cell growth, and cell survival. To establish persistent infection, many viruses have evolved strategies to evade the host's antiviral immune defenses. In the case of hepatitis B virus (HBV), which can cause chronic infection in the liver, immune evasion strategies used by the virus are not fully understood. It has recently been reported that the polymerase of HBV (Pol) inhibits interferon-β (IFN-β) activity by disrupting the interaction between IKKε and the DDX3. In the current study, we found that HBV Pol suppressed NF-κB signaling, which can also contribute to IFN-β production. HBV Pol did not alter the level of NF-κB expression, but it prevented NF-κB subunits involved in both the canonical and non-canonical NF-κB pathways from entering the nucleus. Further experiments demonstrated that HBV Pol preferentially suppressed the activity of the IκB kinase (IKK) complex by disrupting the association of IKK/NEMO with Cdc37/Hsp90, which is critical for the assembly of the IKK complex and recruitment of the IKK complex to the tumor necrosis factor type 1 receptor (TNF-R1). Furthermore, we found that HBV Pol inhibited the NF-κB-mediated transcription of target genes. Taken together, it is suggested that HBV Pol could counteract host innate immune responses by interfering with two distinct signaling pathways required for IFN-β activation. Our studies therefore shed light on a potential therapeutic target for persistent infection with HBV.
    PLoS ONE 03/2014; 9(3):e91658. DOI:10.1371/journal.pone.0091658 · 3.23 Impact Factor
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    • "Prevents heterodimerization with HIF-1β. [271] CCRP Retains CAR and PXR in the cytoplasm associated to microtubules [258] UNC-45 Favors assembly of myosin and myogenesis [272] Tom70 Facilitates mitochondrial import of proteins [273] CHIP Remodels Hsp90-client proteins targeting them to proteosomal degradation [274] SGT1 Required for kinetochore complex assembly and innate immunity in plants and animals [275] [276] Kinases pp60-vSrc Required for Src-mediated cell transformation [277] Raf1 Essential for Raf-kinase activity and ternary assembly with Cdc37 [278] eEF2-K Prevents aggregation and activates kinase activity [279] p210 Bcr-Abl Stabilizes de complex preventing its proteosomal degradation [280] Akt Essential for kinase activity and stability of complexes with Cdc37 [281] Chk1 Favors kinase activity [282] ErB2 Stabilizes and restrains ErbB2 from interacting with other ErbBs in the absence of ligand [283] [284] PDK Stabilizes PDK without affecting the intrinsic enzymatic activity of kinase [285] IκB kinase (IKK) Favors assembly, translocation, and activation of IKKs [286] IGF1R Permits the transduction of the signaling cascade of the receptor [287] Insulin R Receptor trafficking to cytosol. Mobility in the endoplasmic reticulum during maturation [288] [289] VEGFR Favors the development of focal contacts at the receptor site via FAK activation [290] PDGFR Required for receptor maturation and oligomerization with cdc37 [291] [292] TrkA Favors the localization of the receptor in the cell surface [293] Cdk1 Forms complexes with cdc37 [294] JAK Forms complexes with cdc37 [295] p38 Forms complexes with cdc37 attenuating p38 autophosphorylation [296] PKC Required for phosphorylation, stability, mitochondrial and nuclear import [94] [297] [298] DNA-PK Proapoptotic response [217] PARK Possible enhancer of Akt-dependent actions [299] CMDKs Required for fungus transformation [300] Cdk4 Stabilizes complexes with cdc37 [301] MEKK (o MAP3k) Stabilizes complexes and favors kinase activity [302] EPHA7-R Required for kinase activity [303] GSK3 Required for autophosphorylation and stability [235] [304] Structural proteins Histones Induces chromatin condensation [305] Actin Modulates microfilaments assembly [306] Myosin Favors myofilaments assembly and myogenesis [307] Tubulin Protects against thermal denaturation and preserves microtubule polymerization [308] Lamin A/C Possible post-translational modifications [309] Vimentin Prevents cleavage by caspases [310] Keratins Enables protein unfolding and translocation to lysosomes [311] Neurofilaments Prevents protein aggregation and axonal degeneration [312] Nup62 Favors interaction of the GR with the nuclear pore complex and its nuclear translocation [171] Others p23 Client protein stabilization/maturation. "
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    ABSTRACT: The term molecular chaperone was first used to describe the ability of nucleoplasmin to prevent the aggregation of histones with DNA during the assembly of nucleosomes. Subsequently, the name was extended to proteins that mediate the post-translational assembly of oligomeric complexes protecting them from denaturation and/or aggregation. Hsp90 is a 90-kDa molecular chaperone that represents the major soluble protein of the cell. In contrast to most conventional chaperones, Hsp90 functions as a refined sensor of protein function and its principal role in the cell is to facilitate biological activity to properly folded client proteins that already have a preserved tertiary structure. Consequently, Hsp90 is related to basic cell functions such as cytoplasmic transport of soluble proteins, translocation of client proteins to organelles, and regulation of the biological activity of key signalling factors such as protein kinases, ubiquitin ligases, steroid receptors, cell cycle regulators, transcription factors. A growing amount of evidence links the protective action of this molecular chaperone to mechanisms related to posttranslational modifications of soluble nuclear factors as well as histones. In this article, we discuss some aspects of the regulatory action of Hsp90 on transcriptional regulation and how this effect could have impacted genetic assimilation mechanism in some organisms.
    Biochimica et Biophysica Acta 01/2014; 1839(2). DOI:10.1016/j.bbagrm.2013.12.006 · 4.66 Impact Factor
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    • "For example, Hsp70 interacts with IκBα and p65 subunits (Guzhova et al., 1997), while Hsp27 and Hsp90 regulates TNF alpha through IKK (Dodd et al., 2009). Additionally, it is suggested that Hsp 0 s are key regulators of NF-κB activity (Chen and Gao, 2002; Kim et al., 2013; Tam et al., 2012; Xiaoxia et al., 2002). Although previous studies report binary interactions between GRP78 and NF-κB pathway members (Bouwmeester et al., 2004; Rual et al., 2005; Tieri et al., 2012; Fig. S3), the significance and role of these interactions remain unclear. "
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    ABSTRACT: GRP78 participates in multiple functions in the cell during normal and pathological conditions, controlling calcium homeostasis, protein folding and Unfolded Protein Response. GRP78 is located in the endoplasmic reticulum, but it can change its location under stress, hypoxic and apoptotic conditions. NF-κB represents the keystone of the inflammatory process and regulates the transcription of several genes related with apoptosis, differentiation, and cell growth. The possible relationship between GRP78-NF-κB could support and explain several mechanisms that may regulate a variety of cell functions, especially following brain injuries. Although several reports show interactions between NF-κB and Heat Shock Proteins family members, there is a lack of information on how GRP78 may be interacting with NF-κB, and possibly regulating its downstream activation. Therefore, we assessed the computational predictions of the GRP78 (Chain A) and NF-κB complex (IkB alpha and p65) protein-protein interactions. The interaction interface of the docking model showed that the amino acids ASN 47, GLU 215, GLY 403 of GRP78 and THR 54, ASN 182 and HIS 184 of NF-κB are key residues involved in the docking. The electrostatic field between GRP78-NF-κB interfaces and Molecular Dynamic simulations support the possible interaction between the proteins. In conclusion, this work shed some light in the possible GRP78-NF-κB complex indicating key residues in this crosstalk, which may be used as an input for better drug design strategy targeting NF-κB downstream signaling as a new therapeutic approach following brain injuries.
    Journal of Theoretical Biology 12/2013; 345. DOI:10.1016/j.jtbi.2013.12.010 · 2.12 Impact Factor
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