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Molecular and Cellular Biology, August 2002, p. 5813-5825, Vol. 22, No. 16
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.16.5813-5825.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Zinc Finger Domain of NEMO Is Selectively Required for NF-{kappa}B Activation by UV Radiation and Topoisomerase Inhibitors

Tony T. Huang,1 Shelby L. Feinberg,2 Sainath Suryanarayanan,1 and Shigeki Miyamoto1,2*

Programs in Molecular and Cellular Pharmacology,1 Cellular and Molecular Biology, Department of Pharmacology, University of Wisconsin—Madison, Madison, Wisconsin 53706-15322

Received 8 March 2002/ Returned for modification 15 April 2002/ Accepted 10 May 2002

Exposure of mammalian cells to UV radiation was proposed to stimulate the transcription factor NF-{kappa}B by a unique mechanism. Typically, rapid and strong inducers of NF-{kappa}B, such as tumor necrosis factor alpha (TNF-{alpha}) and bacterial lipopolysaccharide (LPS), lead to rapid phosphorylation and proteasomal degradation of its inhibitory protein, I{kappa}B{alpha}. In contrast, UV, a relatively slower and weaker inducer of NF-{kappa}B, was suggested not to require phosphorylation of I{kappa}B{alpha} for its targeted degradation by the proteasome. We now provide evidence to account for this peculiar degradation process of I{kappa}B{alpha}. The phospho-I{kappa}B{alpha} generated by UV is only detectable by expressing a {Delta}F-box mutant of the ubiquitin ligase ß-TrCP, which serves as a specific substrate trap for serine 32 and 36 phosphorylated I{kappa}B{alpha}. In agreement with this finding, we also find that the I{kappa}B kinase (IKK) phospho-acceptor sites on I{kappa}B{alpha}, core components of the IKK signalsome, and IKK catalytic activity are all required for UV signaling. Furthermore, deletion and point mutation analyses reveal that both the amino-terminal IKK-binding and the carboxy-terminal putative zinc finger domains of NEMO (IKK{gamma}) are critical for UV-induced NF-{kappa}B activation. Interestingly, the zinc finger domain is also required for NF-{kappa}B activation by two other slow and weak inducers, camptothecin and etoposide. In contrast, the zinc finger module is largely dispensable for NF-{kappa}B activation by the rapid and strong inducers LPS and TNF-{alpha}. Thus, we suggest that the zinc finger domain of NEMO likely represents a point of convergence for signaling pathways initiated by slow and weak NF-{kappa}B-activating conditions.

* Corresponding author. Mailing address: Department of Pharmacology, University of Wisconsin—Madison, 3795 Medical Sciences Center, 1300 University Ave., Madison, WI 53706-1532. Phone: (608) 262-9281. Fax: (608) 262-1257. E-mail: smiyamot{at}facstaff.wisc.edu.

Molecular and Cellular Biology, August 2002, p. 5813-5825, Vol. 22, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.16.5813-5825.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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