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

The human cytomegalovirus proteins US2 and US11 have co-opted 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 proteins may utilize 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.

Pubmed ID: 19121997

Authors

  • Oresic K
  • Ng CL
  • Tortorella D

Journal

The Journal of biological chemistry

Publication Data

February 27, 2009

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI060905
  • Agency: NIAID NIH HHS, Id: U19 AI062623

Mesh Terms

  • Aspartic Acid Endopeptidases
  • Astrocytoma
  • Endoplasmic Reticulum
  • Glycosylation
  • Histocompatibility Antigens Class I
  • Humans
  • Immunoprecipitation
  • Membrane Glycoproteins
  • Membrane Proteins
  • Membrane Transport Proteins
  • Protein Transport
  • Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Subcellular Fractions
  • Tumor Cells, Cultured
  • Ubiquitin
  • Viral Envelope Proteins
  • Viral Proteins