A cytomegalovirus glycoprotein re‐routes MHC class I complexes to lysosomes for degradation

Mouse cytomegalovirus (MCMV) early gene expression interferes with the major histocompatibility complex class I (MHC class I) pathway of antigen presentation. Here we identify a 48 kDa type I transmembrane glycoprotein encoded by the MCMV early gene m06, which tightly binds to properly folded β2‐microglobulin (β2m)‐associated MHC class I molecules in the endoplasmic reticulum (ER). This association is mediated by the lumenal/transmembrane part of the protein. gp48–MHC class I complexes are transported out of the ER, pass the Golgi, but instead of being expressed on the cell surface, they are redirected to the endocytic route and rapidly degraded in a Lamp‐1+ compartment. As a result, m06‐expressing cells are impaired in presenting antigenic peptides to CD8+ T cells. The cytoplasmic tail of gp48 contains two di‐leucine motifs. Mutation of the membrane‐proximal di‐leucine motif of gp48 restored surface expression of MHC class I, while mutation of the distal one had no effect. The results establish a novel viral mechanism for downregulation of MHC class I molecules by directly binding surface‐destined MHC complexes and exploiting the cellular di‐leucine sorting machinery for lysosomal degradation.

[1]  B. Hoflack,et al.  Mechanisms of protein sorting and coat assembly: insights from the clathrin-coated vesicle pathway. , 1998, Current opinion in cell biology.

[2]  U. Koszinowski,et al.  Immune evasion by cytomegalovirus--survival strategies of a highly adapted opportunist. , 1998, Trends in microbiology.

[3]  F. Brodsky,et al.  Interactions between HIV1 Nef and vacuolar ATPase facilitate the internalization of CD4. , 1998, Immunity.

[4]  K. von Figura,et al.  A di‐leucine‐based motif in the cytoplasmic tail of LIMP‐II and tyrosinase mediates selective binding of AP‐3 , 1998, The EMBO journal.

[5]  C. Geisler,et al.  Regulation and Function of the CD3γ DxxxLL Motif: A Binding Site for Adaptor Protein-1 and Adaptor Protein-2 in Vitro , 1997, The Journal of cell biology.

[6]  A. McMichael,et al.  Evasion of Cytotoxic T Lymphocyte (CTL) Responses by Nef-dependent Induction of Fas Ligand (CD95L) Expression on Simian Immunodeficiency Virus–infected Cells , 1997, The Journal of experimental medicine.

[7]  P. Cresswell,et al.  The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[8]  U. Koszinowski,et al.  A viral ER-resident glycoprotein inactivates the MHC-encoded peptide transporter. , 1997, Immunity.

[9]  P. A. Peterson,et al.  The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP. , 1997, Immunity.

[10]  P. Cresswell,et al.  Misfolded major histocompatibility complex class I heavy chains are translocated into the cytoplasm and degraded by the proteasome. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[11]  H. Ploegh,et al.  A mouse cytomegalovirus glycoprotein, gp34, forms a complex with folded class I MHC molecules in the ER which is not retained but is transported to the cell surface , 1997, The EMBO journal.

[12]  J. Skowroński,et al.  Separable functions of Nef disrupt two aspects of T cell receptor machinery: CD4 expression and CD3 signaling , 1997, The EMBO journal.

[13]  T. Rapoport,et al.  Sec6l-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction , 1996, Nature.

[14]  B. Barrell,et al.  Analysis of the complete DNA sequence of murine cytomegalovirus , 1996, Journal of virology.

[15]  H. Ploegh,et al.  Intermediates in the Assembly and Degradation of Class I Major Histocompatibility Complex (MHC) Molecules Probed with Free Heavy Chain–specific Monoclonal Antibodies , 1996, The Journal of experimental medicine.

[16]  K. Smith,et al.  Invariant chain association with MHC class I: preference for HLA class I/beta 2-microglobulin heterodimers, specificity, and influence of the MHC peptide-binding groove. , 1996, Journal of immunology.

[17]  H. Ploegh,et al.  Human cytomegalovirus US3 impairs transport and maturation of major histocompatibility complex class I heavy chains. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[18]  P. A. Peterson,et al.  Human cytomegalovirus inhibits antigen presentation by a sequential multistep process. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Bogyo,et al.  The Human Cytomegalovirus US11 Gene Product Dislocates MHC Class I Heavy Chains from the Endoplasmic Reticulum to the Cytosol , 1996, Cell.

[20]  F. Lemonnier,et al.  Endocytosis of major histocompatibility complex class I molecules is induced by the HIV–1 Nef protein , 1996, Nature Medicine.

[21]  G. Geginat,et al.  Identification of the mouse cytomegalovirus genomic region affecting major histocompatibility complex class I molecule transport , 1995, Journal of virology.

[22]  M. Jackson,et al.  A Role for Acidic Residues in Di-leucine Motif-based Targeting to the Endocytic Pathway (*) , 1995, The Journal of Biological Chemistry.

[23]  J. Yewdell,et al.  Herpes simplex virus turns off the TAP to evade host immunity , 1995, Nature.

[24]  P. A. Peterson,et al.  A viral inhibitor of peptide transporters for antigen presentation , 1995, Nature.

[25]  N. Saijo,et al.  Construction of a novel bovine papillomavirus vector without detectable transforming activity suitable for gene transfer. , 1995, Human gene therapy.

[26]  M. Sugita,et al.  Association of the Invariant Chain with Major Histocompatibility Complex Class I Molecules Directs Trafficking to Endocytic Compartments (*) , 1995, The Journal of Biological Chemistry.

[27]  U. Koszinowski,et al.  Identification and expression of a murine cytomegalovirus early gene coding for an Fc receptor , 1994, Journal of virology.

[28]  O. Bakke,et al.  Targeting of membrane proteins to endosomes and lysosomes. , 1994, Trends in cell biology.

[29]  M. J. Clague,et al.  Vacuolar ATPase activity is required for endosomal carrier vesicle formation. , 1994, The Journal of biological chemistry.

[30]  U. Koszinowski,et al.  Cytomegalovirus prevents antigen presentation by blocking the transport of peptide-loaded major histocompatibility complex class I molecules into the medial-Golgi compartment , 1992, The Journal of experimental medicine.

[31]  U. Koszinowski,et al.  Efficient processing of an antigenic sequence for presentation by MHC class I molecules depends on its neighboring residues in the protein , 1991, Cell.

[32]  O. Bakke,et al.  MHC class II-associated invariant chain contains a sorting signal for endosomal compartments , 1990, Cell.

[33]  U. Koszinowski,et al.  Presentation of CMV immediate-early antigen to cytolytic T lymphocytes is selectively prevented by viral genes expressed in the early phase , 1989, Cell.

[34]  J. Strominger,et al.  Constitutive endocytosis of HLA class I antigens requires a specific portion of the intracytoplasmic tail that shares structural features with other endocytosed molecules. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[35]  E. Yunis,et al.  Receptor-like nature of class I HLA: endocytosis via coated pits. , 1988, Journal of immunology.

[36]  S. Hoffstein,et al.  Major histocompatibility complex class I molecules internalized via coated pits in T lymphocytes , 1987, Nature.

[37]  U. Koszinowski,et al.  The 89,000-Mr murine cytomegalovirus immediate-early protein activates gene transcription , 1986, Journal of virology.

[38]  P. Möller,et al.  Differential expression of Ia and Ia-associated invariant chain in mouse tissues after in vivo treatment with IFN-gamma. , 1986, Journal of immunology.

[39]  H. Burgert,et al.  An adenovirus type 2 glycoprotein blocks cell surface expression of human histocompatibility class I antigens , 1985, Cell.

[40]  F. Momburg,et al.  Generation and TAP-mediated transport of peptides for major histocompatibility complex class I molecules. , 1998, Advances in immunology.

[41]  David C. Johnson,et al.  Herpesvirus evasion of the immune system. , 1998, Current topics in microbiology and immunology.

[42]  U. Koszinowski,et al.  A mouse cytomegalovirus glycoprotein retains MHC class I complexes in the ERGIC/cis-Golgi compartments. , 1997, Immunity.

[43]  M. Foti,et al.  The HIV-1 Nef protein acts as a connector with sorting pathways in the Golgi and at the plasma membrane. , 1997, Immunity.

[44]  P. A. Peterson,et al.  Inhibition of MHC class I antigen presentation by viral proteins , 1997, Journal of Molecular Medicine.

[45]  C. Watts,et al.  Capture and processing of exogenous antigens for presentation on MHC molecules. , 1997, Annual review of immunology.

[46]  H. Ploegh,et al.  Generation, translocation, and presentation of MHC class I-restricted peptides. , 1995, Annual review of biochemistry.

[47]  P. Seglen.  Inhibitors of lysosomal function. , 1983, Methods in enzymology.