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Immune evasion in the endoplasmic re...

Furman, Margo Herron.

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Immune evasion in the endoplasmic reticulum: Dissecting the strategies of human cytomegalovirus.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Immune evasion in the endoplasmic reticulum: Dissecting the strategies of human cytomegalovirus./
Author:	Furman, Margo Herron.
Description:	300 p.
Notes:	Adviser: Hidde Ploegh.
Contained By:	Dissertation Abstracts International63-04B.
Subject:	Biology, Cell. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3051165
ISBN:	0493656715

Immune evasion in the endoplasmic reticulum: Dissecting the strategies of human cytomegalovirus.
Furman, Margo Herron.

Immune evasion in the endoplasmic reticulum: Dissecting the strategies of human cytomegalovirus. - 300 p.

Adviser: Hidde Ploegh.

Thesis (Ph.D.)--Harvard University, 2002.

The US2 and US11 gene products of HCMV bind to MHC class I molecules in the endoplasmic reticulum (ER) and target them for proteasomal degradation. An <italic>in vitro</italic> translation-based cell-free system that recapitulates US2- and US11-mediated degradation was developed to dissect the mechanism by which MHC class I heavy chains are transported into the cytosol. <italic> In vitro</italic> translated MHC class I HLA-A2 molecules are exported from microsomes prepared from human cell lines that express US2 or US11. In the presence of proteasome inhibitors, deglycosylated heavy chain intermediates indistinguishable from those seen in intact US2- and US11-expressing cells accumulate in the supernatants of cell-free reactions in a cytosol-dependent manner. Microsomes derived from canine pancreas support the degradation of CD4 by HIV Vpu but do not efficiently support US2 and US11 activity, suggesting that membrane-specific factors are required for US2- and US11-mediated dislocation.

ISBN: 0493656715Subjects--Topical Terms:

1017686
Biology, Cell.

Immune evasion in the endoplasmic reticulum: Dissecting the strategies of human cytomegalovirus.
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005 20110425
008 110425s2002 eng d
020 $a 0493656715
035 $a (UnM)AAI3051165
035 $a AAI3051165
040 $a UnM $c UnM
100 1 $a Furman, Margo Herron. $3 1251312
245 1 0 $a Immune evasion in the endoplasmic reticulum: Dissecting the strategies of human cytomegalovirus.
300 $a 300 p.
500 $a Adviser: Hidde Ploegh.
500 $a Source: Dissertation Abstracts International, Volume: 63-04, Section: B, page: 1647.
502 $a Thesis (Ph.D.)--Harvard University, 2002.
520 $a The US2 and US11 gene products of HCMV bind to MHC class I molecules in the endoplasmic reticulum (ER) and target them for proteasomal degradation. An <italic>in vitro</italic> translation-based cell-free system that recapitulates US2- and US11-mediated degradation was developed to dissect the mechanism by which MHC class I heavy chains are transported into the cytosol. <italic> In vitro</italic> translated MHC class I HLA-A2 molecules are exported from microsomes prepared from human cell lines that express US2 or US11. In the presence of proteasome inhibitors, deglycosylated heavy chain intermediates indistinguishable from those seen in intact US2- and US11-expressing cells accumulate in the supernatants of cell-free reactions in a cytosol-dependent manner. Microsomes derived from canine pancreas support the degradation of CD4 by HIV Vpu but do not efficiently support US2 and US11 activity, suggesting that membrane-specific factors are required for US2- and US11-mediated dislocation.
520 $a The structural requirements for US2- and US11-mediated degradation have been examined. MHC class I truncation mutants lacking 29 residues of the 31-residue cytosolic tail are resistant to US2 and US11 in intact cells. Intermediate truncation mutants show that US11 cannot degrade molecules that have less than 20 tail residues remaining, while US2 can degrade molecules with less than 10 residues. Ablation of the cytosolic tail of US2 renders it unable to catalyze degradation, while a similar mutation in US11 has no effect. Thus US2 and US11 utilize distinct targeting mechanisms to destroy class I heavy chains.
520 $a US2 may preferentially induce the dislocation of folded MHC class I complexes. US2, but not US11, triggers the ubiquitination of folded MHC class I molecules prior to their dislocation from the ER. One, two, and three ubiquitin moieties are added to the cytosolic tail of heavy chains. Replacement of lysines in the heavy chain cytosolic tail with arginines prevents ubiquitination, but does not prevent degradation. Therefore the initial dislocation step may be independent of ubiquitination.
520 $a To investigate another HCMV gene product that may have an immunomodulatory function, we expressed HA epitope-tagged US10. HA-US10 is a glycoprotein that is retained in the ER. MHC class I heavy chains co-precipitate with HA-US10. HA-US10 delays the egress of MHC class I molecules from the ER.
590 $a School code: 0084.
650 4 $a Biology, Cell. $3 1017686
650 4 $a Biology, Microbiology. $3 1017734
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Health Sciences, Immunology. $3 1017716
690 $a 0307
690 $a 0379
690 $a 0410
690 $a 0982
710 2 0 $a Harvard University. $3 528741
773 0 $t Dissertation Abstracts International $g 63-04B.
790 $a 0084
790 1 0 $a Ploegh, Hidde, $e advisor
791 $a Ph.D.
792 $a 2002
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3051165