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Viruses manipulate the central machineries of host cells to their advantage. They prevent host cell antiviral responses to create a favorable environment for their survival and propagation. Measles virus (MV) encodes two nonstructural proteins MV-V and MV-C known to counteract the host interferon response and to regulate cell death pathways. Several molecular mechanisms underlining MV-V regulation of innate immunity and cell death pathways have been proposed, whereas MV-C host-interacting proteins are less studied. We suggest that some cellular factors that are controlled by MV-C protein during viral replication could be components of innate immunity and the cell death pathways. To determine which host factors are targeted by MV-C, we captured both direct and indirect host-interacting proteins of MV-C protein. For this, we used a strategy based on recombinant viruses expressing tagged viral proteins followed by affinity purification and a bottom-up mass spectrometry analysis. From the list of host proteins specifically interacting with MV-C protein in different cell lines, we selected the host targets that belong to immunity and cell death pathways for further validation. Direct protein interaction partners of MV-C were determined by applying protein complementation assay and the bioluminescence resonance energy transfer approach. As a result, we found that MV-C protein specifically interacts with p65–iASPP protein complex that controls both cell death and innate immunity pathways and evaluated the significance of these host factors on virus replication., Graphical Abstract, Highlights • Measles virus controls immune response and cell death pathways to achieve replication. • Host proteins interaction network with measles virulence factor C protein. • Cellular p65–iASPP complex is targeted by measles virus C protein., In Brief Control of measles virus infection and measles-based oncolytic therapy are possible, thanks to the existence of a safe and efficient live attenuated vaccine. Molecular mechanisms that make this vaccine to be so efficient are yet to be determined. We show that the measles C protein is responsible for the establishment of complex networks of interactions with the host cell. We suggest that the C protein binding to the p65–iASPP protein complex controls the host cell death and innate immunity pathways.

Additional file 6: Figure S6. Isotyping of humoral IgG responses at day 42 in mice immunized with 30 YU N-PbCS yeast lysates. L-non-adjuvanted lysate formulation administered 5 times weekly, AL-alum-adjuvanted lysate formulation administered 3 times bi-weekly. Bars correspond to median values per group.

Additional file 2: Figure S2. Survival curves of mice immunized with 30 YU of N-PbCS, PbCS, N or WT yeast lysates in Experiment I after challenge with GFP + Pb sporozoites.

Additional file 3: Figure S3. Isotyping of humoral IgG responses at day 42: IgG1 (A), IgG2a (B), and IgG2b (C) in mice immunized with 30, 150 and 300 YU of N-PbCS non-adjuvanted yeast lysates. Bars correspond to median values per group. “x3”-three bi-weekly immunizations; “x5”-five weekly immunizations. Mouse sera were analysed at 1/103 dilution. Asterisks (*) indicate significant median differences (one symbol for p

Additional file 5: Figure S5. Second challenge of the mouse that survived the first challenge in Experiment II. Log10 values of parasitemia in the mouse immunized with 300 YU N-PbCS yeast lysate that survived first infection at day 42 (“N-PbCS survivor”) and three naive mice at day 5 following infection at day 118 with 104 GFP+ P. berghei sporozoites.

Additional file 7: Figure S7. Kinetics of humoral anti-PbCS responses in immunized mice with N-PbCS yeast lysates adjuvanted with alum. OD450nm are expressed in log10 scale. Arrows indicate immunization schedule. Mouse sera were analysed at 1/103 dilution.

Additional file 4: Figure S4. Survival curves of immunized mice in Experiment II after challenge with GFP + Pb sporozoites. (A)-30 YU N-PbCS, N or WT yeast lysates 3 times bi-weekly; (B)-30 YU N-PbCS, N or WT yeast lysates 5 times weekly; (C)-150 YU N-PbCS, N or WT yeast lysates 5 times weekly; (D)-300 YU N-PbCS, N or WT yeast lysates 5 times weekly.

Additional file 8: Figure S8. Survival curves of immunized mice in Experiment III after challenge with GFP + Pb sporozoites. Mice were immunized 3 times bi-weekly with (A)-50 YU N-PbCS or N yeast lysates; (B)-100 YU N-PbCS or N yeast lysates; (C)-150 YU N-PbCS, N or WT yeast lysates: in comparison to mice immunized with the adjuvant alone (Alum group) and naive mice.