Viral manipulation of protein degradation machinery in the endoplasmic reticulum

2005 2005

Other formats: Order a copy

Abstract (summary)

Proteins that fail to pass quality control in the endoplasmic reticulum (ER) are destroyed in the cytosol by the proteasome. The human cytomegalovirus-encoded proteins US2 and US11 co-opt this cellular pathway to eliminate class I major histocompatibility (MHC) products as a means to escape immune detection. Examination of US11 domains important for function revealed that the lumenal portion of US11 mediates binding to the class I MHC heavy chain, while the transmembrane domain (TMD) is essential for catalyzing dislocation. The US11 TMD contains a polar glutamine residue (Q192) that is absolutely required for dislocation of the class I MHC heavy chain, which suggests that a single polar amino acid within the US11 TMD mediates an interaction with the dislocation machinery.

In an effort to identify factors that participate in US11-mediated dislocation, a biochemical search for US11-interacting proteins was performed. I identified Derlin-1, which is homologous to yeast Der1p, a protein that assists in the degradation of misfolded ER proteins. Derlin-1 associates with the class I MHC heavy chain during dislocation across the ER membrane. US11 uses its TMD to recruit the class I MHC heavy chain to Derlin-1, thus providing specificity for class I MHC products and increasing the rate constant of degradation. A dominant-negative Derlin-1 construct interferes with US11-, but not US2-dependent degradation of class I MHC products. Degradation of additional misfolded ER membrane proteins requires Derlin-1 function.

Derlin-2, like Derlin-1, is an ER membrane protein that associates with polyubiquitinated dislocation substrates on their way out of the ER. Derlin-2 forms a complex with the p97 AAA ATPase and with the mammalian equivalents of the yeast Hrd1p/Hrd3p ER membrane-associated ubiquitin ligase complex, required in yeast for the degradation of misfolded ER proteins. The Derlin proteins are capable of forming homo- and hetero-oligomers, indicating that these proteins may form higher order structures within the ER membrane. Derlin proteins form complexes that move misfolded ER proteins to the cytosol, as well as ubiquitinate and extract the substrates prior to proteasomal proteolysis.

Indexing (details)

Cellular biology;
0379: Cellular biology
0982: Immunology
0410: Microbiology
Identifier / keyword
Health and environmental sciences; Biological sciences; Cytomegalovirus; Derlin-1; Endoplasmic reticulum; Protein degradation; Viral
Viral manipulation of protein degradation machinery in the endoplasmic reticulum
Lilley, Brendan Neil
Number of pages
Publication year
Degree date
School code
DAI-B 66/05, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
9780542114243, 0542114240
Ploegh, Hidde
Harvard University
University location
United States -- Massachusetts
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
Access the complete full text

You can get the full text of this document if it is part of your institution's ProQuest subscription.

Try one of the following:

  • Connect to ProQuest through your library network and search for the document from there.
  • Request the document from your library.
  • Go to the ProQuest login page and enter a ProQuest or My Research username / password.