Postrepression activation of NF-kappa B requires the amino-terminal nuclear export signal specific to I kappa B alpha

One of the most prominent NF-kappaB target genes in mammalian cells is the gene encoding one of its inhibitor proteins, I kappaB alpha. The increased synthesis of I kappaB alpha leads to postinduction repression of nuclear NF -kappaB activity. However, it is unknown why I kappaB alpha, among multiple I kappaB family members, is involved in this process and what significance this feedback regulation has beyond terminating NF-kappaB activity. Herein , we report an important I kappaB alpha -specific function dictated by its amino-terminal nuclear export sequence (N-NES). The I kappaB alpha N-NES is necessary for the postinduction export of nuclear NF-kappaB, which is a cr itical event in reestablishing a permissive condition for NF-kappaB to be r apidly reactivated. We show that although I kappaB alpha and another I kapp aB member, I kappaB beta, can enter the nucleus and repress NF-kappaB DNA-b inding activity during the postinduction phase, only I kappaB alpha allows the efficient export of nuclear NF-kappaB, Moreover, snapping the N-termina l region of I kappaB beta for the corresponding I kappaB alpha sequence is sufficient for the I kappaB chimera protein to export NF-kappaB similarly t o I kappaB alpha during the postinduction state. Our findings provide a mec hanistic explanation of why I kappaB alpha but not other I kappaB members i s crucial for postrepression activation of NF-kappaB. We propose that this I kappaB alpha -specific function is important for certain physiological an d pathological conditions where NF-kappaB needs to be rapidly reactivated.