Herpesviruses induce aggregation and selective autophagy of host signalling proteins NEMO and RIPK1 as an immune-evasion mechanism.
Elena MuscolinoRebekka SchmitzStefan LorochEnrico CaraglianoCarola SchneiderMatteo RizzatoYoung-Hyun KimEva KrauseVanda Juranić LisnićAlbert SickmannRudolph ReimerEleonore OstermannWolfram BrunePublished in: Nature microbiology (2019)
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.
Keyphrases
- epstein barr virus
- protein protein
- binding protein
- oxidative stress
- cell death
- signaling pathway
- amino acid
- transcription factor
- protein kinase
- endoplasmic reticulum stress
- small molecule
- immune response
- diabetic rats
- diffuse large b cell lymphoma
- high resolution
- cell proliferation
- induced pluripotent stem cells
- artificial intelligence
- big data
- pi k akt