Postrepression activation of NF-κB requires the amino-terminal nuclear export signal specific to IκBα

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 critical event in reestablishing a permissive condition for NF-kappaB to be rapidly reactivated. We show that although I kappaB alpha and another I kappaB member, I kappaB beta, can enter the nucleus and repress NF-kappaB DNA-binding activity during the postinduction phase, only I kappaB alpha allows the efficient export of nuclear NF-kappaB, Moreover, snapping the N-terminal 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 to I kappaB alpha during the postinduction state. Our findings provide a mechanistic explanation of why I kappaB alpha but not other I kappaB members is crucial for postrepression activation of NF-kappaB. We propose that this I kappaB alpha -specific function is important for certain physiological and pathological conditions where NF-kappaB needs to be rapidly reactivated.