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27 mars 2018: 1 événement

  • Département Virologie

    Mardi 27 mars 11:00-12:30 - Wolfram Brune - Heinrich Pette Institute, Leibniz Institute for Experimental Virology

    Viral induced protein aggregation and selective autophagy for the inhibition of cell death and inflammation

    Résumé : Murine cytomegalovirus (MCMV) encodes a multifunctional protein called M45. This protein interacts with receptor-interacting protein kinase 1 (RIPK1) and RIPK3 to inhibit the induction of programmed necrosis in response to viral infection. M45 also blocks proinflammatory NF-κB signalling by interacting with the regulatory subunit of the IKK complex, NEMO, and redirecting it to autophagosomes. However, the molecular mechanism of autophagy induction and selective NEMO degradation by M45 remained to be determined. We now show that degradation occurs in two steps. First, M45 interacting with NEMO and RIPK1 causes their accumulation in the detergent insoluble fraction, most likely as misfolded protein aggregates. A conserved sequence motif with the C-terminal part of M45 was identified as responsible for this process. In the second step, insoluble aggregates are targeted to autophagosomes for degradation in lysosomes. This process requires the interaction of M45 with Vps26B, a component of the retromer complex. Vps26B serves as a selective autophagy receptor by interacting with the key autophagy marker LC3-II via the adaptor protein TBC1D5. Indeed, we show that M45-induced NEMO and RIPK1 degradation was inhibited in Vps26b or TBC1D5 deficient cells. Collectively the data suggest that M45 recruits the retromer component Vps26B to promote the degradation of insoluble NEMO and RIPK1 aggregates via the adaptor protein TBC1D5.

    Lieu : Salle de séminaire bâtiment 14C - Campus de Gif-sur-Yvette

    En savoir plus : Département Virologie