Herpes simplex virus 1 ICP6 impedes TNF receptor 1-induced necrosome assembly during compartmentalization to detergent-resistant membrane vesicles

• Type of Material: Article
• Authors: Mohammed K Ali, Emory University; Linda Roback, Emory University; Edward Mocarski, Emory University
• Language: English
• Date: 2019-01-18
• Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
• Publication Version: Final Published Version
• Copyright Statement: © 2019 Ali et al.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.RA118.004651
• Title of Journal or Parent Work: JOURNAL OF BIOLOGICAL CHEMISTRY
• Volume: 294
• Issue: 3
• Start Page: 991
• End Page: 1004
• Grant/Funding Information: This work was supported by an Emory–Onyx (Amgen) Alliance Fund Award (to M. A.) and Public Health Service Grants AI020211 and AI118853 from the National Institutes of Health (to E. S. M.).
• Keywords: CELL-DEATH; PROGRAMMED NECROSIS; cell death; necrosome; NECROPTOSIS; tumor necrosis factor (TNF); caveolin; PHOSPHORYLATION; Science & Technology; MLKL; APOPTOSIS; MIXED LINEAGE KINASE; SUPPRESSION; Life Sciences & Biomedicine; RIPK3; DOMAIN-LIKE PROTEIN; oligomerization; Biochemistry & Molecular Biology; lipid raft; RHIM-signaling; RIPK1; REQUIRES; detergent-resistant membranes
• Research Categories: Health Sciences, Oncology; Chemistry, Biochemistry; Biology, Molecular

Abstract

Receptor-interacting protein (RIP) kinase 3 (RIPK3)– dependent necroptosis directs inflammation and tissue injury, as well as anti-viral host defense. In human cells, herpes simplex virus 1 (HSV1) UL39-encoded ICP6 blocks RIP homotypic interacting motif (RHIM) signal transduction, preventing this leakage form of cell death and sustaining viral infection. TNF receptor 1 (TNFR1)-induced necroptosis is known to require the formation of a RIPK1–RIPK3–mixed lineage kinase domain–like pseudokinase (MLKL) signaling complex (necrosome) that we find compartmentalizes exclusively to caveolin-1–associated detergent-resistant membrane (DRM) vesicles in HT-29 cells. Translocation proceeds in the presence of RIPK3 kinase inhibitor GSK840 or MLKL inhibitor necrosulfonomide but requires the kinase activity, as well as RHIM signaling of RIPK1. ICP6 impedes the translocation of RIPK1, RIPK3, and MLKL to caveolin-1– containing DRM vesicles without fully blocking the activation of RIPK3 or phosphorylation of MLKL. Consistent with the important contribution of RIPK1 RHIM-dependent recruitment of RIPK3, overexpression of RHIM-deficient RIPK3 results in phosphorylation of MLKL, but this does not lead to either translocation or necroptosis. Combined, these data reveal a critical role of RHIM signaling in the recruitment of the MLKL-containing necrosome to membrane vesicle–associated sites of aggregation. A similar mechanism is predicted for other RHIM-containing signaling adaptors, Z-nucleic acid– binding protein 1 (ZBP1) (also called DAI and DLM1), and TIR domain– containing adapter–inducing interferon- (TRIF).