Targeted
inhibition of proteasome activity is essential for survival of yeast during
stationary phase.
Monika Bajorek (1), Dan Finley (2), Michael Glickman (1)
(1) Biology, The Technion, I.I.T., Haifa, 32000, Israel
(glickman@tx.technion.ac.il); (2) Dept. of Cell biology, Harvard Med. School
200 Longwood Ave. Boston MA 02115 USA
Upon starvation, yeast cells enter a stationary phase (SP) during which the synthesis of proteins is dramatically decreased. We show that a parallel decrease in intracellular proteasome-dependent proteolysis also occurs. The reduction in proteolysis is correlated with a programmed disassembly of proteasome holoenzymes into their 20S core particle (CP) and 19S regulatory particle (RP) components. Upon encounter of stationary cells with nutrients, proteasomes are rapidly reassembled, and proteolysis resumes prior to cell cycle re-entry. We have generated an 'open channel' mutant proteasome that exhibits faster rates of protein degradation both in vivo and in vitro. In particular, these mutants exhibit persistent proteolysis during SP, unlike their wild-type counterparts. Such unscheduled degradation causes a delay in outgrowth from SP and eventual lethality. In summary, we have found that the ubiquitin-proteasome pathway can be subjected to global down-regulation, that the proteasome is a target of this regulation, and that proteasome down-regulation is required for the survival of stationary phase cells. Maintaining high viability during SP is essential for evolutionary fitness, which may explain the extreme conservation of channel gating residues in proteasomes in eukaryotes.