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A slowly cleaved viral signal peptide acts as a protein-integral immune evasion domain

Author

Listed:
  • Einat Seidel

    (The Hebrew University Medical School, IMRIC)

  • Liat Dassa

    (The Hebrew University Medical School, IMRIC)

  • Shira Kahlon

    (The Hebrew University Medical School, IMRIC)

  • Boaz Tirosh

    (Hebrew University Faculty of Medicine, Hebrew University of Jerusalem)

  • Anne Halenius

    (Medical Center University of Freiburg
    University of Freiburg)

  • Tal Seidel Malkinson

    (Sorbonne Université, Inserm UMRS 1127, CNRS UMR 7225)

  • Ofer Mandelboim

    (The Hebrew University Medical School, IMRIC)

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.

Suggested Citation

  • Einat Seidel & Liat Dassa & Shira Kahlon & Boaz Tirosh & Anne Halenius & Tal Seidel Malkinson & Ofer Mandelboim, 2021. "A slowly cleaved viral signal peptide acts as a protein-integral immune evasion domain," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21983-x
    DOI: 10.1038/s41467-021-21983-x
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