Nuclear-specific degradation of Far1 is controlled by the localization of the F-box protein Cdc4

Part is a bifunctional protein that is required to arrest the cell cycle an d establish cell polarity during yeast mating. Here we show that SCFCdc4 ub iquitylates Farl in the nucleus, which in turn targets the multi-ubiquityla ted protein to 26S proteasomes most likely located at the nuclear envelope. In response to mating pheromones, a fraction of Farl was stabilized after its export into the cytoplasm by Ste21/Msn5. Preventing nuclear export dest abilized Farl, while conversely cytoplasmic Part was stabilized, although t he protein was efficiently phosphorylated in a Cdc28-Cln-dependent manner. The core SCF subunits Cdc53, Hrt1 and Skp1 were distributed in the nucleus and the cytoplasm, whereas the F-box protein Cdc4 was exclusively nuclear, A cytoplasmic form of Cdc4 was unable to complement the growth defect of cd c4-1 cells, but it was sufficient to degrade Part in the cytoplasm, Our res ults illustrate the importance of subcellular localization of F-box protein s, and provide an example of how an extracellular signal regulates protein stability at the level of substrate localization.