The NF-B/Rel family of transcription factors plays a critical role in the development of a normal immune response (39, 65, 75). The nuclear activities of NF-B/Rel proteins are regulated from the cytoplasmic compartment by interactions with a set of inhibitory proteins, including IB␣ and IB␤ (26,71,74). Cellular stimulation leads to the rapid degradation of these conditionally labile inhibitors and the transit of active NF-B/Rel complexes to the nucleus (9,26,74). Primary structural and functional analyses have indicated that IB␣ and IB␤ are organized as tripartite molecules containing (i) an N-terminal regulatory domain required for induced proteolytic breakdown (15,16,18,21,49,62,68,73,76), (ii) a central Rel-interactive domain composed of six ankyrin repeat motifs (25,33,35), and (iii) a highly acidic C-terminal region which is rich in proline, glutamic acid, serine, and threonine residues (30, 72). Sequences of the latter type, termed PEST domains, have been implicated as cis-acting proteolytic signals that determine the metabolic turnover rates of specific proteins (56, 57). However, the function of the PEST domains in IB proteins remains controversial. In contrast to prior reports (16, 76), recent mutational studies have suggested that the PEST domain of IB␣ is dispensable for its signal-induced turnover in activated cells (68). Other experiments have indicated that phosphorylation of the IB␣ PEST domain by casein kinase II regulates basal rather than induced turnover of this inhibitor (46,48,64).