The Molecular and Functional Characterization of a Degron in IkappaBalpha /
- Author(s): Fortmann, Karen Teresa
- et al.
Cells are capable of rapidly responding to changes in their environment, including the presence of pathogens or noxious conditions. Molecular signaling pathways that regulate these responses show highly dynamic patterns of activity. Indeed, the controls of half-life and protein degradation are hallmarks of many signaling pathways. In the case of the NF[kappa]B regulatory pathway, the key mediator of inflammatory responses, the inhibitor proteins I[kappa]B[alpha], -[beta], and -ε are known to be regulated by signal-responsive mechanisms freeing NF[kappa]B. Recent work also indicates that I[kappa]B[alpha] is synthesized in excess in resting cells to ensure that NF[kappa]B activity remains effectively inhibited. Rapid degradation of the excess I[kappa]B is critical so that NF[kappa]B activation can proceed rapidly when inflammatory responses are needed. Cellular protein degradation is catalyzed by the proteasome, a large molecular machine. Proteins are usually targeted for degradation by a specific post-translational modification, the covalent attachment of the small molecule ubiquitin. In this dissertation I report that I[kappa]B[alpha] does not require such modifications for its rapid degradation, but instead relies on a specific amino-acid sequence, termed a degron, that targets even heterologous proteins to the proteasome. Interestingly these amino acids are buried within the I[kappa]B[alpha]-NF[kappa]B complex, thus stabilizing I[kappa]B[alpha], and allowing it to effectively inhibit NF[kappa]B. This work describes a novel determinant of protein half-life control and shows that it is amenable to regulation by a post-translational mechanism to stabilize the target protein. In examining the other I[kappa]B family members, I show that while I[kappa]B[beta] may undergo similar control, I[kappa]B[epsilon] is in fact a stable protein that maybe less suited to ensure NF[kappa]B inhibition in resting cells