Activation of a membrane-bound transcription factor by regulated ubiquitin/proteasome-dependent processing

Processing of integral membrane proteins in order to liberate active protei ns is of exquisite cellular importance. Examples are the processing events that govern sterol regulation, Notch signaling, the unfolded protein respon se, and APP fragmentation linked to Alzheimer's disease. In these cases, th e proteins are thought to be processed by regulated intramembrane proteolys is, involving site-specific, membrane-localized proteases. Here we show tha t two homologous yeast transcription factors SPT23 and MGA2 are made as dor mant ER/nuclear membrane-localized precursors and become activated by a com pletely different mechanism that involves ubiquitin/proteasome-dependent pr ocessing. SPT23 and MGA2 are relatives of mammalian NF-kappa B and control unsaturated fatty acid levels. Intriguingly, proteasome-dependent processin g of SPT23 is regulated by fatty acid pools, suggesting that the precursor itself or interacting partners are sensors of membrane composition or fluid ity.