TY  - JOUR
AU  - Seidel, Einat
AU  - Dassa, Liat
AU  - Kahlon, Shira
AU  - Tirosh, Boaz
AU  - Halenius, Anne
AU  - Seidel Malkinson, Tal
AU  - Mandelboim, Ofer
TI  - A slowly cleaved viral signal peptide acts as a protein-integral immune evasion domain.
JO  - Nature Communications
VL  - 12
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-02458
SP  - 2061
PY  - 2021
N1  - #DKFZ-MOST-Ca186#
AB  - 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.
KW  - Cell Line
KW  - Cytomegalovirus: immunology
KW  - Cytomegalovirus: physiology
KW  - Cytomegalovirus Infections: immunology
KW  - Endoplasmic Reticulum: metabolism
KW  - Endoplasmic Reticulum-Associated Degradation
KW  - Histocompatibility Antigens Class I: metabolism
KW  - Humans
KW  - Immune Evasion
KW  - Killer Cells, Natural: immunology
KW  - Kinetics
KW  - Membrane Glycoproteins: chemistry
KW  - Membrane Glycoproteins: metabolism
KW  - Mutant Proteins: chemistry
KW  - Mutant Proteins: metabolism
KW  - Protein Binding
KW  - Protein Domains
KW  - Protein Sorting Signals
KW  - Proteins: metabolism
KW  - Proteolysis
KW  - Solubility
KW  - Viral Proteins: chemistry
KW  - Viral Proteins: metabolism
KW  - Histocompatibility Antigens Class I (NLM Chemicals)
KW  - MHC class I-related chain A (NLM Chemicals)
KW  - Membrane Glycoproteins (NLM Chemicals)
KW  - Mutant Proteins (NLM Chemicals)
KW  - Protein Sorting Signals (NLM Chemicals)
KW  - Proteins (NLM Chemicals)
KW  - SEL1L protein, human (NLM Chemicals)
KW  - US9 protein, Human herpesvirus 5 (NLM Chemicals)
KW  - Viral Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:33824318
C2  - pmc:PMC8024260
DO  - DOI:10.1038/s41467-021-21983-x
UR  - https://inrepo02.dkfz.de/record/306229
ER  -