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

doi:10.1038/s41467-021-21983-x

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 journal › Article › peer-review

6 Scopus citations

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.

Original language	American English
Article number	2061
Pages (from-to)	1-19
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21983-x
State	Published - 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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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.",

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AU - Seidel, Einat

AU - Dassa, Liat

AU - Kahlon, Shira

AU - Tirosh, Boaz

AU - Halenius, Anne

AU - Seidel Malkinson, Tal

AU - Mandelboim, Ofer

N1 - 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).

PY - 2021/12/1

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N2 - 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.

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.

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

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