No 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 β 2 -microglobulin (β 2 m)-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.

No abstract

The Adenoviridae family includes clinically important viruses associated with acute episodes of pharyngitis, conjunctivitis, diarrhea, and cystitis in immunocompetent individuals. In immunosuppressed patients, particularly pediatric transplant recipients, adenoviruses (Ads) are capable of systemic viremic spread that produces significant levels of morbidity and mortality. More than 50 human Ads have been described, of which the common species C serotypes 2 and 5 (HAdV-2 and HAdV-5) have been studied most intensively (52), and demonstrated to encode functions that act in vitro and in vivo to promote evasion of both innate and adaptive host immune responses (11). Immunomodulatory functions are concentrated in the early transcription unit E3 (33, 51). An E3 protein, E3/19K, became an immunological paradigm when it was demonstrated to impede cell surface antigen presentation by retaining the major histocompatibility class I complex (MHC-I) in the endoplasmic reticulum (ER) (1,8,10,17). E3/ 10.4K and E3/14.5K (the RID complex) together remove Fas, tumor necrosis factor-related apoptosis-inducing ligand receptors 1 and 2, and the epidermal growth factor receptor from the cell surface and promote their subsequent degradation in lysosomes (5,12,18,24,44,45,51). Moreover, E3/14.7K suppresses inflammation and cytolysis by inhibiting tumor necrosis factor alphamediated signaling independently of the RID complex (11,26).We are interested in the role of NK cells in controlling Ad infections. NK cells are a heterogeneous population of cells expressing a wide range of activating and inhibitory receptors. NKG2D is a homodimeric activating receptor that is ubiquitously expressed on NK cells, ␥␦ T cells, and NKT cells and also on certain ␣␤ T-cell subsets (3). To date, seven human cellular NKG2D ligands (NKG2DLs) have been identified: the MHC-I chain-related A (MICA) and B (MICB) proteins, the UL16 binding proteins ULBP1 to -3, and the retinoic acid early inducible proteins E (ULBP4) and G (2, 3, 16). While MICA and MICB are closely related, sharing 84% amino acid (aa) identity and similar tertiary structures (25, 32), they are also highly polymorphic, with 61 MICA and 30 MICB alleles having been described (IMGT;

Adenoviruses (