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Vol. 12, Issue 10, 3226-3241, October 2001
§ and
*Department of Biological Chemistry and Molecular Pharmacology,
Harvard Medical School, and Department of Cancer Biology, The
Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and
Proteolytic activation of membrane-bound transcription factors has
emerged as an important mechanism for the regulation of gene
expression. Two membrane-bound transcription factors regulated in this
manner are the Saccharomyces cerevisiae proteins Mga2p and Spt23p, which direct transcription of the The Salk Institute, La Jolla, California 92037
9-fatty acid
desaturase gene OLE1. We now show that a
membrane-associated complex containing the highly conserved Npl4p,
Ufd1p, and Cdc48p proteins mediates the proteasome-regulated cleavage
of Mga2p and Spt23p. Mutations in NPL4,
UFD1, and CDC48 cause a block in Mga2p
and Spt23p processing, with concomitant loss of OLE1
expression. Taken together, our data indicate that the Npl4 complex may
serve to target the proteasome to the ubiquitinated endoplasmic
reticulum membrane-bound proteins Mga2p and Spt23p. Given the recent
finding that NPL4 is allelic to the ERAD gene
HRD4, we further propose that this NPL4
function extends to all endoplasmic reticulum-membrane-associated
targets of the proteasome.
Institute for Molecular
Biology and Tumor Research, Philipps-University Marburg, 35037 Marburg,
Germany;
§Illumina, Inc., San Diego, California 92121.
Corresponding author. E-mail address:
pamela_silver{at}dfci.harvard.edu.
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