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

Einat Seidel, Liat Dassa, Shira Kahlon, Boaz Tirosh, Anne Halenius, Tal Seidel Malkinson and Ofer Mandelboim ()
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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
Tal Seidel Malkinson: Sorbonne Université, Inserm UMRS 1127, CNRS UMR 7225
Ofer Mandelboim: The Hebrew University Medical School, IMRIC

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21983-x

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