Herpesviruses induce aggregation and selective autophagy of host signalling proteins NEMO and RIPK1 as an immune-evasion mechanism

Nat Microbiol. 2020 Feb;5(2):331-342. doi: 10.1038/s41564-019-0624-1. Epub 2019 Dec 16.

Abstract

Viruses manipulate cellular signalling by inducing the degradation of crucial signal transducers, usually via the ubiquitin-proteasome pathway. Here, we show that the murine cytomegalovirus (Murid herpesvirus 1) M45 protein induces the degradation of two cellular signalling proteins, the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) essential modulator (NEMO) and the receptor-interacting protein kinase 1 (RIPK1), via a different mechanism: it induces their sequestration as insoluble protein aggregates and subsequently facilitates their degradation by autophagy. Aggregation of target proteins requires a distinct sequence motif in M45, which we termed 'induced protein aggregation motif'. In a second step, M45 recruits the retromer component vacuolar protein sorting 26B (VPS26B) and the microtubule-associated protein light chain 3 (LC3)-interacting adaptor protein TBC1D5 to facilitate degradation of aggregates by selective autophagy. The induced protein aggregation motif is conserved in M45-homologous proteins of several human herpesviruses, including herpes simplex virus, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, but is only partially conserved in the human cytomegalovirus UL45 protein. We further show that the HSV-1 ICP6 protein induces RIPK1 aggregation and degradation in a similar fashion to M45. These data suggest that induced protein aggregation combined with selective autophagy of aggregates (aggrephagy) represents a conserved viral immune-evasion mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / immunology
  • Autophagy-Related Protein 5 / deficiency
  • Autophagy-Related Protein 5 / genetics
  • Cells, Cultured
  • HEK293 Cells
  • Herpesviridae / immunology*
  • Herpesviridae / metabolism
  • Herpesviridae / pathogenicity
  • Herpesvirus 1, Human / immunology
  • Herpesvirus 1, Human / metabolism
  • Herpesvirus 1, Human / pathogenicity
  • Host Microbial Interactions / immunology
  • Humans
  • Immune Evasion
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / immunology*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Muromegalovirus / immunology
  • Muromegalovirus / metabolism
  • Muromegalovirus / pathogenicity
  • Protein Aggregates / immunology
  • Proteolysis
  • Receptor-Interacting Protein Serine-Threonine Kinases / chemistry
  • Receptor-Interacting Protein Serine-Threonine Kinases / immunology*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Ribonucleotide Reductases / genetics
  • Ribonucleotide Reductases / immunology
  • Ribonucleotide Reductases / metabolism
  • Viral Proteins / genetics
  • Viral Proteins / immunology
  • Viral Proteins / metabolism

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Intracellular Signaling Peptides and Proteins
  • NEMO protein, mouse
  • Protein Aggregates
  • Viral Proteins
  • herpes simplex virus type 1-protein ICP6
  • Ribonucleotide Reductases
  • m45 protein, Mouse cytomegalovirus 1
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse