Signaling of a varicelloviral factor across the endoplasmic reticulum membrane induces destruction of the peptide-loading complex and immune evasion.
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.
Loch
Sandra
S
Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, D-60438, Frankfurt/Main, Germany.
Klauschies
Florian
F
Schölz
Christian
C
Verweij
Marieke C
MC
Wiertz
Emmanuel J H J
EJ
Koch
Joachim
J
Tampé
Robert
R
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000276:immunology* / Q000378:metabolism*; D007425:Intracellular Membranes / Q000276:immunology*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000276:immunology*; D011485:Protein Binding; D016415:Sequence Alignment; D015398:Signal Transduction / Q000276:immunology*; D018411:Spodoptera; D018140:Varicellovirus / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D010455:Peptides; D014759:Viral Envelope Proteins