%0 Journal Article
%A Seidel, Einat
%A Dassa, Liat
%A Kahlon, Shira
%A Tirosh, Boaz
%A Halenius, Anne
%A Seidel Malkinson, Tal
%A Mandelboim, Ofer
%T A slowly cleaved viral signal peptide acts as a protein-integral immune evasion domain.
%J Nature Communications
%V 12
%N 1
%@ 2041-1723
%C [London]
%I Springer Nature
%M DKFZ-2025-02458
%P 2061
%D 2021
%Z #DKFZ-MOST-Ca186#
%X 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.
%K Cell Line
%K Cytomegalovirus: immunology
%K Cytomegalovirus: physiology
%K Cytomegalovirus Infections: immunology
%K Endoplasmic Reticulum: metabolism
%K Endoplasmic Reticulum-Associated Degradation
%K Histocompatibility Antigens Class I: metabolism
%K Humans
%K Immune Evasion
%K Killer Cells, Natural: immunology
%K Kinetics
%K Membrane Glycoproteins: chemistry
%K Membrane Glycoproteins: metabolism
%K Mutant Proteins: chemistry
%K Mutant Proteins: metabolism
%K Protein Binding
%K Protein Domains
%K Protein Sorting Signals
%K Proteins: metabolism
%K Proteolysis
%K Solubility
%K Viral Proteins: chemistry
%K Viral Proteins: metabolism
%K Histocompatibility Antigens Class I (NLM Chemicals)
%K MHC class I-related chain A (NLM Chemicals)
%K Membrane Glycoproteins (NLM Chemicals)
%K Mutant Proteins (NLM Chemicals)
%K Protein Sorting Signals (NLM Chemicals)
%K Proteins (NLM Chemicals)
%K SEL1L protein, human (NLM Chemicals)
%K US9 protein, Human herpesvirus 5 (NLM Chemicals)
%K Viral Proteins (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:33824318
%2 pmc:PMC8024260
%R 10.1038/s41467-021-21983-x
%U https://inrepo02.dkfz.de/record/306229