Cytomegalovirus prevents antigen presentation by blocking the transport of peptide-loaded major histocompatibility complex class I molecules into the medial-Golgi compartment.

Abstract

SummarySelective expression of murine cytomegalovirus (MCMV) immediate-early (IE) genes leads to the presentation by the major histocompatibility complex (MHC) class I molecule L a of a peptide derived from MCMV IE protein pp89 (Reddehase, M. J., J. B. Rothbard, and U. H. Koszinowski. 1989. Nature (Lond.). 337:651). Characterization of endogenous antigenic peptides identified the pp89 peptide as the nonapeptide msYPHFMFFNLt76 (del Val, M., H.-J. Schlicht, T. Ruppert, M. J. Reddehase, and U. H. . Cell. 66:1145. Subsequent expression of MCMV early genes prevents presentation of pp89 (del Val, M., K. Mfinch, M. J. Reddehase, and U. H. Koszinowski. 1989. Cell. 58:305). We report on the mechanism by which MCMV early genes interfere with antigen presentation. Expression of the IE promoter-driven bacterial gene lacZ by recombinant MCMV subjected antigen presentation of B-galactosidase to the same control and excluded antigen specificity. The La-dependent presence of naturally processed antigenic peptides also in nonpresenting cells located the inhibitory function subsequent to the step of antigen processing. The finding that during the E phase of MCMV gene expression the MHC class I heavy chain glycosylation remained in an Endo H-sensitive form suggested a block within the endoplasmic reticulum/c/s-Golgi compartment. The failure to present antigenic peptides was explained by a general retention of nascent assembled trimolecular MHC class I complexes. Accordingly, at later stages of infection a significant decrease of surface MHC class I expression was seen, whereas other membrane glycoproteins remained unaffected. Thus, MCMV E genes endow this virus with an effective immune evasion potential. These results also indicate that the formation of the trimolecular complex of MHC dass I heavy chain, ~2-microglobulin, and the finally trimmed peptide is completed before entering the medial-Golgi compartment.

The murine cytomegalovirus immunoevasin gp40 binds MHC class I molecules to retain them in the early secretory pathway

“…There was no evidence of any impairment of peptide loading in the presence of gp40 for either allotype such as it is seen for tapasin or TAP deficiency ( Fritzsche et al, 2015). Thus, in agreement with earlier reports (del Val et al, 1992;Ziegler et al, 2000), we find that gp40 does not impair class I folding, maturation, or peptide binding.…”

“…Given that at least D b does not become EndoF1-resistant at all in gp40-containing cells, we conclude that the compact juxtanuclear steady-state location observed for D b and K b in Fig. 1B is a pre-medial-Golgi compartment, most likely the ERGIC and/or the cis-Golgi, as suggested previously (del Val et al, 1992), and in agreement with our microscopic analysis.…”

Coordinated Function of Murine Cytomegalovirus Genes Completely Inhibits CTL Lysis

“…All three VIPRs function to inhibit CD8 T cell recognition of infected cells, but each VIPR employs a unique strategy to accomplish this task. m152 primarily functions by blocking MHC class I transport from the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) to the Golgi, resulting in an accumulation of peptide-loaded class I molecules in the ERGIC and a reduction in cell surface class I expression (2)(3)(4). Interestingly, although m152 has a pronounced effect on MHC class I transport, no direct biochemical interaction between m152/gp40 and MHC class I has ever been demonstrated.…”

Molecular characterization of two human autoantigens: unique cDNAs encoding 95- and 160-kD proteins of a putative family in the Golgi complex.

“…An attractive feature to the study of Golgi antigens is the knowledge that viruses, including HIV (29), coronaviruses (30), rubella (31), and various others (reviewed in reference 32), are processed in, and disrupt (33,34), the Golgi complex. Observations that certain viruses induce anti-Golgi antibodies in mice (35,36), and that individuals infected with EBV (12) and the HIV-I virus (13) bear anti-Golgi antibodies, add incentive to the study of the molecular characteristics of the Golgi autoantigens.…”