An HRD/DER- independent quality control mechanism involves
Rsp5p-dependent ubiquitination and ER-Golgi transport.
Cole
Haynes, Antony Cooper
School of Biological Sciences, Univ. of
Missouri-Kansas City , 5007 Rockhill Road, Kansas City, Mo 64110, USA
The Endoplasmic Reticulum associated degradation (ERAD) machinery
degrades misfolded proteins from the ER. We have identified a new
pathway of ERAD that functions separately from the HRD/DER
pathway comprised of Hrd1p, Hrd3p, Der1p and Ubc7p. This pathway termed
HIP (Hrd1p Independent Proteolysis) is capable of recognizing and
degrading both lumenal and integral membrane proteins that misfold in
the ER. CPY* over-expression likely saturates the HRD/DER
pathway and activates the HIP pathway so that the slowed degradation
kinetics of CPY* in an hrd1* strain is restored to wild-type
kinetics upon CPY* over-expression. Substrates of HIP require vesicular
trafficking between the ER and Golgi prior to degradation by the
ubiquitin-proteasome system. Ubiquitination of HIP substrates does not
involve the HRD/DER pathway ubiquitin ligase Hrd1p but instead
utilizes another ubiquitin ligase, Rsp5p. HIP is regulated by the
Unfolded Protein Response (UPR) as Ire1p is necessary for the
degradation of over-expressed CPY*, however not CPY* that is expressed
at normal levels. Both the HIP and HRD/DER pathways contribute
to the degradation of CPY*, and only by eliminating both is CPY*
degradation completely blocked. We have shown that two pathways (
HRD/DER and HIP) contribute to the quality control of proteins in
the ER and both are regulated to some degree by the UPR. Work
addressing the relationships between both pathways as well as new
components of each will be presented.
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