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Abstract
Cytotoxic T lymphocytes eliminate infected cells upon surface display of antigenic peptides on major histocompatibility complex I molecules. To promote immune evasion, UL49.5 of several varicelloviruses interferes with the pathway of major histocompatibility complex I antigen processing. However, the inhibition mechanism has not been elucidated yet. Within the macromolecular peptide-loading complex we identified the transporter associated with antigen processing (TAP1 and TAP2) as the prime target of UL49.5. Moreover, we determined the active oligomeric state and crucial elements of the viral factor. Remarkably, the last two residues of the cytosolic tail of UL49.5 are essential for endoplasmic reticulum (ER)-associated proteasomal degradation of TAP. However, this process strictly requires additional signaling of an upstream regulatory element in the ER lumenal domain of UL49.5. Within this new immune evasion mechanism, we show for the first time that additive elements of a small viral factor and their signaling across the ER membrane are essential for targeted degradation of a multi-subunit membrane complex.
Highlights
Porter associated with antigen processing (TAP, ABCB2/3), a heterodimeric ATP-binding cassette complex comprised of TAP1 and TAP2 [3]
Tel.: 49-69-798-29475; Fax: 49-69-798-29495; E-mail: tampe@em.uni-frankfurt.de. 3 The abbreviations used are: MHC, major histocompatibility complex; BHV, bovine herpesvirus; ER, endoplasmic reticulum; HCMV, human cytomegalovirus; PLC, peptide-loading complex; TAP, transporter associated with antigen processing; YFP, yellow fluorescent protein; IRES, internal ribosome entry site; GFP, green fluorescent protein; EGFP, enhanced GFP; YFP, yellow fluorescent protein; BiFC, bimolecular fluorescence complementation; PE, phycoerythrin; MJS, Mel JuSo; phosphate-buffered saline (PBS), phosphatebuffered saline; fluorescence-activated cell sorting (FACS), fluorescence-activated cell sorter; Tricine, N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine
After peptide loading onto MHC I molecules in the ER, peptide-MHC complexes dissociate from the PLC and traffic to the cell surface for inspection by cytotoxic T lymphocytes
Summary
TAP [24], comprises a signal sequence, a short ER lumenal domain (36 amino acids), a transmembrane region (23 amino acids), and a short cytoplasmic tail of 16 amino acids [27]. UL49.5 inhibits peptide transport and is involved in proteasomal degradation of components of the PLC in a process that requires the cytosolic tail of UL49.5 [24]. We identified distinct domains and critical elements of UL49.5, whose concerted action across the ER membrane is essential for proteasomal degradation of the multi-subunit PLC
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