TRAM1 participates in human cytomegalovirus US2- and US11-mediated dislocation of an endoplasmic reticulum membrane glycoprotein

Kristina Oresic, Caroline L. Ng, Domenico Tortorella

Research output: Contribution to journalArticle

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Abstract

The human cytomegalovirus proteins US2 and US11 have coopted endoplasmic reticulum (ER) quality control to facilitate the destruction of major histocompatibility complex class I heavy chains. The class I heavy chains are dislocated from the ER to the cytosol, where they are deglycosylated and subsequently degraded by the proteasome. We examined the role of TRAM1 (translocating chain-associated membrane protein-1) in the dislocation of class I molecules using US2- and US11-expressing cells. TRAM1 is an ER protein initially characterized for its role in processing nascent polypeptides. Co-immunoprecipitation studies demonstrated that TRAM1 can complex with the wild type US2 and US11 proteins as well as deglycosylated and polyubiquitinated class I degradation intermediates. In studies using US2- and US11-TRAM1 knockdown cells, we observed an increase in levels of class I heavy chains. Strikingly, increased levels of glycosylated heavy chains were observed in TRAM1 knockdown cells when compared with control cells in a pulse-chase experiment. In fact, US11-mediated class I dislocation was more sensitive to the lack of TRAM1 than US2. These results provide further evidence that these viral proteinsmayutilize distinct complexes to facilitate class I dislocation. For example, US11-mediated class I heavy chain degradation requires Derlin-1 and SEL1L, whereas signal peptide peptidase is critical for US2-induced class I destabilization. In addition, TRAM1 can complex with the dislocation factors Derlin-1 and signal peptide peptidase. Collectively, the data support a model in which TRAM1 functions as a cofactor to promote efficient US2-and US11-dependent dislocation of major histocompatibility complex class I heavy chains.

Original languageEnglish (US)
Pages (from-to)5905-5914
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number9
DOIs
StatePublished - Feb 27 2009

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Membrane Glycoproteins
Cytomegalovirus
Endoplasmic Reticulum
Membrane Proteins
Major Histocompatibility Complex
Degradation
Proteasome Endopeptidase Complex
Immunoprecipitation
Quality Control
Cytosol
Quality control
Proteins
Peptides
Molecules
Processing

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

TRAM1 participates in human cytomegalovirus US2- and US11-mediated dislocation of an endoplasmic reticulum membrane glycoprotein. / Oresic, Kristina; Ng, Caroline L.; Tortorella, Domenico.

In: Journal of Biological Chemistry, Vol. 284, No. 9, 27.02.2009, p. 5905-5914.

Research output: Contribution to journalArticle

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