A Cytomegalovirus Glycoprotein Re-routes MHC Class I Complexes to Lysosomes for Degradation

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 1999 Feb 18

PMID 10022849

Citations 101

Authors

U Reusch

W Muranyi

P Lucin

H G Burgert

H Hengel

U H Koszinowski

Affiliations

Soon will be listed here.

Abstract

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 beta2-microglobulin (beta2m)-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.

Citing Articles

The Quest for Immunity: Exploring Human Herpesviruses as Vaccine Vectors.

Kamel M, Munds R, Verma M Int J Mol Sci. 2023; 24(22).

PMID: 38003300 PMC: 10671728. DOI: 10.3390/ijms242216112.

Exploring the Potential of Cytomegalovirus-Based Vectors: A Review.

Zeng J, Jaijyan D, Yang S, Pei S, Tang Q, Zhu H Viruses. 2023; 15(10).

PMID: 37896820 PMC: 10612100. DOI: 10.3390/v15102043.

Murine cytomegalovirus downregulates ERAAP and induces an unconventional T cell response to self.

Geiger K, Manoharan M, Coombs R, Arana K, Park C, Lee A Cell Rep. 2023; 42(4):112317.

PMID: 36995940 PMC: 10539480. DOI: 10.1016/j.celrep.2023.112317.

Membraneless Compartmentalization of Nuclear Assembly Sites during Murine Cytomegalovirus Infection.

Mahmutefendic Lucin H, Lukanovic Juric S, Marcelic M, Stimac I, Viduka I, Blagojevic Zagorac G Viruses. 2023; 15(3).

PMID: 36992475 PMC: 10053344. DOI: 10.3390/v15030766.

Host-Adapted Gene Families Involved in Murine Cytomegalovirus Immune Evasion.

Becker S, Fink A, Podlech J, Reddehase M, Lemmermann N Viruses. 2022; 14(1).

PMID: 35062332 PMC: 8781790. DOI: 10.3390/v14010128.

References

Del Val M, Schlicht H, Ruppert T, Reddehase M, Koszinowski U . Efficient processing of an antigenic sequence for presentation by MHC class I molecules depends on its neighboring residues in the protein. Cell. 1991; 66(6):1145-53. DOI: 10.1016/0092-8674(91)90037-y. View

Borgne R, Hoflack B . Mechanisms of protein sorting and coat assembly: insights from the clathrin-coated vesicle pathway. Curr Opin Cell Biol. 1998; 10(4):499-503. DOI: 10.1016/s0955-0674(98)80065-3. View

Del Val M, Munch K, Reddehase M, Koszinowski U . Presentation of CMV immediate-early antigen to cytolytic T lymphocytes is selectively prevented by viral genes expressed in the early phase. Cell. 1989; 58(2):305-15. DOI: 10.1016/0092-8674(89)90845-3. View

Vega M, Strominger J . Constitutive endocytosis of HLA class I antigens requires a specific portion of the intracytoplasmic tail that shares structural features with other endocytosed molecules. Proc Natl Acad Sci U S A. 1989; 86(8):2688-92. PMC: 286983. DOI: 10.1073/pnas.86.8.2688. View

Jones T, Wiertz E, Sun L, Fish K, Nelson J, Ploegh H . Human cytomegalovirus US3 impairs transport and maturation of major histocompatibility complex class I heavy chains. Proc Natl Acad Sci U S A. 1996; 93(21):11327-33. PMC: 38057. DOI: 10.1073/pnas.93.21.11327. View

Hengel H, Koopmann J, Flohr T, Muranyi W, Goulmy E, Hammerling G . A viral ER-resident glycoprotein inactivates the MHC-encoded peptide transporter. Immunity. 1997; 6(5):623-32. DOI: 10.1016/s1074-7613(00)80350-7. View

Wiertz E, Tortorella D, Bogyo M, Yu J, Mothes W, Jones T . Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature. 1996; 384(6608):432-8. DOI: 10.1038/384432a0. View

Sandoval I, Bakke O . Targeting of membrane proteins to endosomes and lysosomes. Trends Cell Biol. 1994; 4(8):292-7. DOI: 10.1016/0962-8924(94)90220-8. View

Xu X, Screaton G, Gotch F, Dong T, Tan R, Almond N . Evasion of cytotoxic T lymphocyte (CTL) responses by nef-dependent induction of Fas ligand (CD95L) expression on simian immunodeficiency virus-infected cells. J Exp Med. 1997; 186(1):7-16. PMC: 2198954. DOI: 10.1084/jem.186.1.7. View

10.

Hengel H, Brune W, Koszinowski U . Immune evasion by cytomegalovirus--survival strategies of a highly adapted opportunist. Trends Microbiol. 1998; 6(5):190-7. DOI: 10.1016/s0966-842x(98)01255-4. View

11.

Seglen P . Inhibitors of lysosomal function. Methods Enzymol. 1983; 96:737-64. DOI: 10.1016/s0076-6879(83)96063-9. View

12.

Honing S, Sandoval I, von Figura K . A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J. 1998; 17(5):1304-14. PMC: 1170479. DOI: 10.1093/emboj/17.5.1304. View

13.

Del Val M, Hengel H, Hacker H, Hartlaub U, Ruppert T, Lucin P . Cytomegalovirus prevents antigen presentation by blocking the transport of peptide-loaded major histocompatibility complex class I molecules into the medial-Golgi compartment. J Exp Med. 1992; 176(3):729-38. PMC: 2119349. DOI: 10.1084/jem.176.3.729. View

14.

Wiertz E, Jones T, Sun L, Bogyo M, Geuze H, Ploegh H . The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell. 1996; 84(5):769-79. DOI: 10.1016/s0092-8674(00)81054-5. View

15.

Hasenkrug K, Cory J, Stimpfling J . Monoclonal antibodies defining mouse tissue antigens encoded by the H-2 region. Immunogenetics. 1987; 25(2):136-9. DOI: 10.1007/BF00364282. View

16.

Bakke O, Dobberstein B . MHC class II-associated invariant chain contains a sorting signal for endosomal compartments. Cell. 1990; 63(4):707-16. DOI: 10.1016/0092-8674(90)90137-4. View

17.

Dietrich J, Kastrup J, Nielsen B, Odum N, Geisler C . Regulation and function of the CD3gamma DxxxLL motif: a binding site for adaptor protein-1 and adaptor protein-2 in vitro. J Cell Biol. 1997; 138(2):271-81. PMC: 2138198. DOI: 10.1083/jcb.138.2.271. View

18.

Koszinowski U, Keil G, Volkmer H, Fibi M, Munch K . The 89,000-Mr murine cytomegalovirus immediate-early protein activates gene transcription. J Virol. 1986; 58(1):59-66. PMC: 252876. DOI: 10.1128/JVI.58.1.59-66.1986. View

19.

Vigna J, Smith K, Lutz C . 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. J Immunol. 1996; 157(10):4503-10. View

20.

Sugita M, Brenner M . Association of the invariant chain with major histocompatibility complex class I molecules directs trafficking to endocytic compartments. J Biol Chem. 1995; 270(3):1443-8. DOI: 10.1074/jbc.270.3.1443. View