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, Ofer Mandelboim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageAmerican English
Article number2061
Pages (from-to)1-19
JournalNature Communications
Issue number1
StatePublished - 1 Dec 2021

Bibliographical note

Funding Information:
This study was supported by the ISF Israel-China grant. Further support came from the GIF foundation, the ICRF professorship grant, the Israeli Science Foundation (Moked), a Ministry of Science Personal Medicine grant, and the DKFZ-MOST grant. E.S. was supported during her work by the Adams Fellowship Program of the Israel Academy of Sciences and Humanities and by the Foulkes Foundation.

Publisher Copyright:
© 2021, The Author(s).


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