Herpesviruses induce aggregation and selective autophagy of host signalling proteins NEMO and RIPK1 as an immune-evasion mechanism.
Animals
Autophagy
/ immunology
Autophagy-Related Protein 5
/ deficiency
Cells, Cultured
HEK293 Cells
Herpesviridae
/ immunology
Herpesvirus 1, Human
/ immunology
Host Microbial Interactions
/ immunology
Humans
Immune Evasion
Intracellular Signaling Peptides and Proteins
/ chemistry
Mice
Mice, Inbred C57BL
Models, Biological
Muromegalovirus
/ immunology
Protein Aggregates
/ immunology
Proteolysis
Receptor-Interacting Protein Serine-Threonine Kinases
/ chemistry
Ribonucleotide Reductases
/ genetics
Viral Proteins
/ genetics
Journal
Nature microbiology
ISSN: 2058-5276
Titre abrégé: Nat Microbiol
Pays: England
ID NLM: 101674869
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
16
01
2019
accepted:
30
10
2019
pubmed:
18
12
2019
medline:
17
7
2020
entrez:
18
12
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31844296
doi: 10.1038/s41564-019-0624-1
pii: 10.1038/s41564-019-0624-1
doi:
Substances chimiques
Atg5 protein, mouse
0
Autophagy-Related Protein 5
0
Intracellular Signaling Peptides and Proteins
0
NEMO protein, mouse
0
Protein Aggregates
0
Viral Proteins
0
herpes simplex virus type 1-protein ICP6
0
Ribonucleotide Reductases
EC 1.17.4.-
m45 protein, Mouse cytomegalovirus 1
EC 1.17.4.-
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
Ripk1 protein, mouse
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
331-342Références
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