Diminished recognition of HLA-A2 proteins lacking a cytoplasmic domain (CY) by A2-restricted, EBV-specific CTLs: possible role of the CY in TAP association

Cannon, Martin J.; Osborn, Criston K.; Nazaruk, Rachel A.; Grigoriev, Vitalii G.; Crew, Mark D.

doi:10.1007/s002510050502

Cited by 2 publications

(1 citation statement)

References 35 publications

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“…It should be noted that class I directly associates with tapasin and not TAP (32), though tapasin and TAP are always detected as a complex in cells that express both (18,32). Sites located in the luminal domains of class I profoundly affect its association with TAP/tapasin (45), although the cytoplasmic tail of class I may also influence association with TAP/tapasin (4 (Fig. 1C).…”

Section: Resultsmentioning

confidence: 99%

Model for the Interaction of Gammaherpesvirus 68 RING-CH Finger Protein mK3 with Major Histocompatibility Complex Class I and the Peptide-Loading Complex

Wang¹,

Lybarger²,

Connors³

et al. 2004

J Virol

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The mK3 protein of gammaherpesvirus 68 and the kK5 protein of Kaposi's sarcoma-associated herpesvirus are members of a family of structurally related viral immune evasion molecules that all possess a RING-CH domain with ubiquitin ligase activity. These proteins modulate the expression of major histocompatibility complex class I molecules (mK3 and kK5) as well as other molecules like ICAM-1 and B7.2 (kK5). Previously, mK3 was shown to ubiquitinate nascent class I molecules, resulting in their rapid degradation, and this process was found to be dependent on TAP and tapasin, endoplasmic reticulum molecules involved in class I assembly. Here, we demonstrate that in murine cells, kK5 does not affect class I expression but does downregulate human B7.2 molecules in a TAP/tapasin-independent manner. These differences in substrate specificity and TAP/tapasin dependence between mK3 and kK5 permitted us, using chimeric molecules, to map the sites of mK3 interaction with TAP/tapasin and to determine the requirements for substrate recognition by mK3. Our findings indicate that mK3 interacts with TAP1 and -2 via their C-terminal domains and with class I molecules via their N-terminal domains. Furthermore, by orienting the RING-CH domain of mK3 appropriately with respect to class I, mK3 binding to TAP/tapasin, rather than the presence of unique sequences in class I, appears to be the primary determinant of substrate specificity.Many viruses have developed elaborate mechanisms to evade immune detection (11,26,40,46). These mechanisms are typically specific for a given type of virus and are highly host adapted (10). Thus, viruses have clearly evolved under the selective pressure of the host immune system to develop counter strategies to prevent their elimination. Given the importance of CD8 ϩ T cells in immune surveillance against many viral infections, it is not surprising that viruses have evolved genes whose products function to block the expression of class I molecules. Recently, a novel family of viral and cellular proteins (termed here the K3 family) has been identified and found to possess E3 ubiquitin (Ub) ligase activity. Several members of this family have been shown to target class I molecules and/or T-cell costimulation molecules for Ub-dependent degradation (3,15,21). E3 Ub ligase activity is conferred to members of the K3 family by a consensus N-terminal sequence encoding a special type of RING (for "really interesting new gene") finger motif, known as the RING-CH type of zinc finger (38), characterized by a cysteine residue in the fourth zinc-coordinating position and a histidine residue in the fifth. Alternatively, this motif has been classified as a subclass of the plant homeodomain (PHD)/leukemia-associated protein (LAP) finger (6). Although proteins in this family are structurally and functionally similar, their target specificities and sites of ubiquitination and degradation are distinct. Understanding how disparate members of the K3 family target different proteins at different subcellular sites is an area o...

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Section: Resultsmentioning

confidence: 99%

Model for the Interaction of Gammaherpesvirus 68 RING-CH Finger Protein mK3 with Major Histocompatibility Complex Class I and the Peptide-Loading Complex

Wang¹,

Lybarger²,

Connors³

et al. 2004

J Virol

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Function of the transport complex TAP in cellular immune recognition

Abele

Tampé

1999

Biochimica et Biophysica Acta (BBA) - Biomembranes

119

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The transporter associated with antigen processing (TAP) is essential for peptide loading onto major histocompatibility complex (MHC) class I molecules by translocating peptides into the endoplasmic reticulum. The MHC-encoded ABC transporter works in concert with the proteasome and MHC class I molecules for the antigen presentation on the cell surface for T cell recognition. TAP forms a heterodimer where each subunit consists of a hydrophilic nucleotide binding domain and a hydrophobic transmembrane domain. The transport mechanism is a multistep process composed of an ATP-independent peptide association step which induces a structural reorganization of the transport complex that may trigger the ATP-driven transport of the peptide into the endoplasmic reticulum lumen. By using combinatorial peptide libraries, the substrate selectivity and the recognition principle of TAP have been elucidated. TAP maximizes the degree of substrate diversity in combination with high substrate affinity. This ABC transporter is also unique as it is closely associated with chaperone-like proteins involved in bonding of the substrate onto MHC molecules. Most interestingly, virus-infected and malignant cells have developed strategies to escape immune surveillance by affecting TAP expression or function.

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Diminished recognition of HLA-A2 proteins lacking a cytoplasmic domain (CY) by A2-restricted, EBV-specific CTLs: possible role of the CY in TAP association

Cited by 2 publications

References 35 publications

Model for the Interaction of Gammaherpesvirus 68 RING-CH Finger Protein mK3 with Major Histocompatibility Complex Class I and the Peptide-Loading Complex

Model for the Interaction of Gammaherpesvirus 68 RING-CH Finger Protein mK3 with Major Histocompatibility Complex Class I and the Peptide-Loading Complex

Function of the transport complex TAP in cellular immune recognition

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