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Vol. 11, Issue 10, 3365-3380, October 2000
and
*Department of Molecular Biophysics and Biochemistry, Yale
University, New Haven, Connecticut 06520; and The Saccharomyces cerevisiae DOA4 gene encodes a
deubiquitinating enzyme that is required for rapid degradation of
ubiquitin-proteasome pathway substrates. Both genetic and biochemical
data suggest that Doa4 acts in this pathway by facilitating ubiquitin
recycling from ubiquitinated intermediates targeted to the proteasome.
Here we describe the isolation of 12 spontaneous extragenic suppressors of the doa4-1 mutation; these involve seven different
genes, six of which were cloned. Surprisingly, all of the cloned
DID (Doa4-independent degradation) genes encode
components of the vacuolar protein-sorting (Vps) pathway. In
particular, all are class E Vps factors, which function in the
maturation of a late endosome/prevacuolar compartment into
multivesicular bodies that then fuse with the vacuole. Four of the six
Did proteins are structurally related, suggesting an overlap in
function. In wild-type and several vps strains,
Doa4-green fluorescent protein displays a cytoplasmic/nuclear
distribution. However, in cells lacking the Vps4/Did6 ATPase, a large
fraction of Doa4-green fluorescent protein, like several other Vps
factors, concentrates at the late endosome-like class E compartment
adjacent to the vacuole. These results suggest an unanticipated
connection between protein deubiquitination and endomembrane protein
trafficking in which Doa4 acts at the late endosome/prevacuolar
compartment to recover ubiquitin from ubiquitinated membrane proteins
en route to the vacuole.
Department
of Biochemistry and Molecular Biology, University of Chicago, Chicago,
Illinois 60637
Corresponding author. E-mail address:
mark.hochstrasser{at}yale.edu.
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