IKAP (IKK-complex associated protein) is a highly conserved scaffold protein, originally described as being part of a complex activating NF-kappa B transcription factor. IKAP was also found to interact with and specifically activate JNK (Jun N-terminal kinase). Furthermore, in yeast and humans, IKAP has been characterized biochemically as part of the 6 subunit Elongator complex associated with active RNA Polymerase II. IKAP (= Elp1 in yeast) seems to be tightly associated with Elp2 (another scaffold protein) and Elp3 acetyl-transferase. A second sub-complex consisting of Elp4-6 was also described. A direct interaction of yeast IKAP with Sec2 (a Rab guanine nucleotide exchange factor (GEF)) involved in secretion has been demonstrated, implicating IKAP and Elongator in a cytoplasmic function and challenging the idea of a nuclear role. Although some interesting implications have been proposed, there is currently no unifying theory for the biochemical function of IKAP.
In humans, mutations in the IKBKAP gene (encoding for IKAP) are responsible for Familial Dysautonomia (FD), an autosomal recessive disorder causing poor development, and progressive degeneration of the sensory and autonomic nervous system. Since IKAP is conserved from worms to humans, insights gained in this study should help understanding this debilitating disease.
We found C. elegans IKAP in a genome wide RNAi suppressor screen for
mig-2(gf) defects resulting in an uncoordinated (unc) phenotype. MIG-2 is a Rho family GTPase involved in cell migration, axon outgrowth and vulva development. IKAP was found to be expressed in cells and developmental stages, where MIG-2 plays crucial roles. Deletion of IKAP caused suppression of movement defects and a significantly improved axon outgrowth of motoneurons in
mig-2(gf) mutants. Furthermore, we have evidence that the conserved ELP2, ELP3 and ELP4 proteins might also be involved in these processes: RNAi experiments demonstrated a suppression of the
mig-2(gf) unc phenotype, similar to IKAP. ELP3 is an acetyl-transferase possibly associated with IKAP. We found a predominantly cytoplasmic localization of IKAP. Known targets for acetylation in the cytoplasm are microtubules, which have a central role in neurons and/or cell migration. We are currently analyzing possible effects of MIG-2 and IKAP on microtubule acetylation.