Mobilization of processed, membrane-tethered SPT23 transcription factor byCDC48(UFD1/NPL4), a ubiquitin-selective chaperone

The OLE pathway of yeast regulates the level of the ER-bound enzyme Delta9- fatty acid desaturase OLE1, thereby, controlling membrane fluidity. A centr al component of this regulon is the transcription factor SPT23, a homolog o f mammalian NF-kappaB. SPT23 is synthesized as an inactive, ER membrane-anc hored precursor that is activated by regulated ubiquitin/proteasome-depende nt processing (RUP). We now show that SPT23 dimerizes prior to processing a nd that the processed molecule, p90, retains its ubiquitin modification and initially remains tethered to its unprocessed, membrane-bound SPT23 partne r. Subsequently, p90 is liberated from its partner for nuclear targeting by the: activity of the chaperone-like CDC48(UFD1/NPL4) complex. Remarkably, this enzyme binds preferentially ubiquitinated substrates, suggesting that CDC48(UFD1/NPL4) is qualified to selectively remove ubiquitin conjugates fr om protein complexes.