Translation Initiator Drags Mad Protein to Destruction

Abstract

Eukaryotic translation initiation factor 4a (eIF 4 A) got its name by functioning to initiate translation, but new evidence shows it to have an independent role influencing the abundance of two Drosophila signaling molecules, the SMAD proteins Mad and Medea. Li and Li were led to this surprising conclusion when exploring an earlier finding that a dominant-negative mutant of eIF 4 A suppressed haploinsufficiency of the gene encoding Decapentaplegic (Dpp), the fly ortholog of BMP (bone morphogenetic protein--a member of the transforming growth factor-β superfamily). Further genetic analysis showed that reduced amounts of eIF 4 A helped compensate for mutations that reduced Dpp signaling in embryos and adult flies. Flies expressing the dominant-negative eIF 4 A had increased amounts of Mad protein, suggesting that the loss of eIF 4 A function was decreasing the degradation of Mad. In keeping with this idea, overexpression of eIF 4 A inhibited Dpp signaling and decreased the abundance of Mad. The authors used various coimmunoprecipitation experiments, including analysis of the endogenous proteins in embryo extracts, to show interaction of eIF 4 A with Mad. Experiments with a dominant-negative form of eIF 4 A that inhibits translation indicated that the effects of eIF 4 A on Dpp signaling are independent of its role in translation. Rather, genetic experiments suggested that eIF 4 A could act synergistically with the ubiquitin E3 ligase DSmurf, which regulates the abundance of Mad by promoting its degradation. The synergy suggests that eIF 4 A influenced the same process, but other experiments showed that eIF 4 A could also influence Mad abundance independently of DSmurf. The authors speculate that eIF 4 A may function as an adaptor to link SMAD proteins to the protein degradation machinery. Affolter and Pyrowolakis provide commentary. J. Li, W. X. Li, A novel function of Drosophila eIF4A as a negative regulator of Dpp/BMP signalling that mediates SMAD degradation. Nat. Cell Biol. 8 , 1407-1414 (2006). [PubMed] M. Affolter, G. Pyrowolakis, eIF4A goes beyond translation. Nat. Cell Biol. 8 , 1319-1321 (2006). [PubMed]