Major histocompatibility complex class I molecules are down-regulated at the cell surface by the K5 protein encoded by Kaposi’s sarcoma-associated herpesvirus/human herpesvirus-8

Haque, Muzammel; Ueda, Keiji; Nakano, K.; Hirata, Yuko; Parravicini, Carlo; Corbellino, Mario; Yamanishi, Koichi

doi:10.1099/0022-1317-82-5-1175

Cited by 74 publications

(63 citation statements)

References 23 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They are localized to the endoplasmic reticulum (ER) but mediate their action distally in the secretory pathway, promoting endocytosis of surface MHC-I chains. This MHC-I downregulation has also been observed recently in cultured PEL cell lines undergoing lytic reactivation of KSHV (37). Because KSHV predominantly infects B lymphocytes (36,38), a cell type competent for antigen presentation to T cells, we hypothesized that this virus may also encode proteins that specifically alter T cell activation.…”

supporting

confidence: 67%

A viral protein that selectively downregulates ICAM-1 and B7-2 and modulates T cell costimulation

Coscoy

Ganem²

2001

J. Clin. Invest.

225

186

View full text Add to dashboard Cite

IntroductionThe generation of an adaptive immune response is a complex process that requires the engagement of T cells with professional antigen-presenting cells (APCs), including dendritic cells, macrophages, and B cells. A key step in this process is the activation of the T cell, mediated by interaction of the T cell antigen receptor (TCR) with antigenic peptides presented by MHC molecules on the APCs (1). Sustained TCR engagement is required to generate the full repertoire of T cell responses, including signal transduction, cytokine generation, and cell proliferation (2, 3). Although the TCRpeptide-MHC interaction affords the requisite specificity for such responses, it does not suffice to ensure the sustained engagement needed for effective activation. First, this interaction is generally of modest affinity, and the number of antigenic complexes on the APC surface can be low (4-8). Second, the presence of abundant and sizeable glycoproteins (e.g., the mucins CD43 and CD45) on cell surfaces poses additional barriers to effective cell-cell contact (9, 10). Finally, there is strong evidence that signaling from the TCR receptor is insufficient for T cell activation (2); costimulatory signals are required from accessory receptors, most notably CD28, by interaction with its ligands B7-1 and B7-2 on the APC surface (11-15). The interaction of LFA-1 with its ligand ICAM-1 is also well known to be an important participant in the activation of T cells (16)(17)(18), lowering the concentration of antigen required for

show abstract

supporting

confidence: 67%

A viral protein that selectively downregulates ICAM-1 and B7-2 and modulates T cell costimulation

Coscoy

Ganem²

2001

J. Clin. Invest.

225

186

View full text Add to dashboard Cite

show abstract

“…Although CD31 expression is abundantly found in KS tumors, including the characteristic spindle cells, which often harbor latent viral genome, 49,50 K5 is also widely expressed in tumor tissue. 51 From our data, we predict that those lesional cells expressing K5 would be CD31 negative, whereas most latently infected cells are K5 negative and CD31 positive.…”

Section: Discussionmentioning

confidence: 66%

Kaposi sarcoma herpesvirus K5 removes CD31/PECAM from endothelial cells

Mansouri

Douglas

Rose

et al. 2006

Blood

View full text Add to dashboard Cite

The transmembrane ubiquitin ligase K5/ MIR2 of Kaposi sarcoma herpesvirus (KSHV) mediates internalization and lysosomal degradation of glycoproteins involved in antigen presentation and costimulation. In endothelial cells (ECs), K5 additionally reduced expression of CD31/ platelet-endothelial cell adhesion molecule (PECAM), an adhesion molecule regulating cell-cell interactions of ECs, platelets, monocytes, and T cells. K5 also reduced EC migration, a CD31-dependent process. Unlike other K5 substrates, both newly synthesized and pre-existing CD31 molecules were targeted by K5. K5 was transported to the cell surface and ubiquitinated pre-existing CD31, resulting in endocytosis and lysosomal degradation. In the endoplasmic reticulum, newly synthesized CD31 was degraded by proteasomes, which required binding of phosphofurin acidic cluster sorting protein-2 (PACS-2) to acidic residues in the carboxyterminal tail of K5. Thus, CD31, a novel target of K5, is efficiently removed from ECs by a dual degradation mechanism that is regulated by the subcellular sorting of the ubiquitin ligase. K5 IntroductionKaposi sarcoma (KS), the most common AIDS-associated malignancy, is characterized by disorganized networks of abnormal microvasculature composed of spindle-shaped cells of endothelial cell (EC) origin. 1 KS herpesvirus (KSHV) is consistently found in KS lesions, suggesting that infection with KSHV is a necessary, but not sufficient, prerequisite for the development of KS. 2 KSHV belongs to the family of ␥2-herpesviruses, or Rhadinoviruses, which includes tumorigenic viruses of primates and rodents. 3 In addition to a generally conserved genomic organization and conservation of essential genes, this group of viruses also shares the characteristic of encoding genes pirated from the genomes of their hosts. Examples are KSHV-encoded homologs of cellular CD21, CD200, chemokines, IL-6, BCL-2, interferon regulatory factors, FLICE inhibitory protein (FLIP), cyclin D, and several DNA synthetic enzymes. 2 These cellular homologs function predominantly in host-virus interactions (eg, regulating viral transformation of the host cell as well as modulation of the host's immune response to the virus). 4 Sequence analysis of 2 related open reading frames (ORFs) in the KSHV genome, K3 and K5, indicated that these genes are also host derived. 5 Studies from a number of laboratories indicated that K3 and K5 function as immunomodulators (reviewed in Früh et al 6 ), hence their alias as modulators of immune recognition (MIR). 7 K3 (MIR1) and K5 (MIR2) are transmembrane-spanning ubiquitinligases that mediate the ubiquitination of cytoplasmic lysines or cysteines of other transmembrane proteins. 7,8 Both K3 and K5 target major histocompatibility complex class I (MHC I) molecules, thereby inhibiting presentation of viral antigen to cytotoxic T cells. 9,10 Similarly, the murine gammaherpesvirus 68 (MHV68), which contains the single K3-related ORF MK3, inhibits antigen presentation to T cells, and deletion of MK3 affects the establishment of vira...

show abstract

“…[25][26][27]. Like other herpesvirus family members, it encodes proteins that block MHC class I expression on the cell surface (28)(29)(30)(31). These are known as modulator of immune recognition (MIR) proteins; MIR1 and MIR2 are expressed during lytic replication and are encoded by the open reading frames K3 and K5, respectively.…”

Section: Introductionmentioning

confidence: 99%