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| Home > Institute Collections > W500 > A slowly cleaved viral signal peptide acts as a protein-integral immune evasion domain. |
| Home > Institute Collections > W500 > A slowly cleaved viral signal peptide acts as a protein-integral immune evasion domain. |
| Journal Article | DKFZ-2025-02458 |
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2021
Springer Nature
[London]
Abstract: Stress can induce cell surface expression of MHC-like ligands, including MICA, that activate NK cells. Human cytomegalovirus (HCMV) glycoprotein US9 downregulates the activating immune ligand MICA*008 to avoid NK cell activation, but the underlying mechanism remains unclear. Here, we show that the N-terminal signal peptide is the major US9 functional domain targeting MICA*008 to proteasomal degradation. The US9 signal peptide is cleaved with unusually slow kinetics and this transiently retained signal peptide arrests MICA*008 maturation in the endoplasmic reticulum (ER), and indirectly induces its degradation via the ER quality control system and the SEL1L-HRD1 complex. We further identify an accessory, signal peptide-independent US9 mechanism that directly binds MICA*008 and SEL1L. Collectively, we describe a dual-targeting immunoevasin, demonstrating that signal peptides can function as protein-integral effector domains.
Keyword(s): Cell Line (MeSH) ; Cytomegalovirus: immunology (MeSH) ; Cytomegalovirus: physiology (MeSH) ; Cytomegalovirus Infections: immunology (MeSH) ; Endoplasmic Reticulum: metabolism (MeSH) ; Endoplasmic Reticulum-Associated Degradation (MeSH) ; Histocompatibility Antigens Class I: metabolism (MeSH) ; Humans (MeSH) ; Immune Evasion (MeSH) ; Killer Cells, Natural: immunology (MeSH) ; Kinetics (MeSH) ; Membrane Glycoproteins: chemistry (MeSH) ; Membrane Glycoproteins: metabolism (MeSH) ; Mutant Proteins: chemistry (MeSH) ; Mutant Proteins: metabolism (MeSH) ; Protein Binding (MeSH) ; Protein Domains (MeSH) ; Protein Sorting Signals (MeSH) ; Proteins: metabolism (MeSH) ; Proteolysis (MeSH) ; Solubility (MeSH) ; Viral Proteins: chemistry (MeSH) ; Viral Proteins: metabolism (MeSH) ; Histocompatibility Antigens Class I ; MHC class I-related chain A ; Membrane Glycoproteins ; Mutant Proteins ; Protein Sorting Signals ; Proteins ; SEL1L protein, human ; US9 protein, Human herpesvirus 5 ; Viral Proteins
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