Fig. 3: The NZF domain of HOIL-1L contributes to LUBAC-mediated cell death protection in concert with the NZF domain of SHARPIN.

A, F HOIL-1L/SHARPIN DKO MEFs stably reconstituted with the indicated proteins were stimulated with TNF-α (2.5 ng/mL) and CHX (20 μg/mL) for the indicated times and analyzed by immunoblotting with the indicated antibodies. Data are representative of three independent experiments. B HOIL-1L/SHARPIN DKO MEFs stably reconstituted with the indicated proteins were stimulated with TNF-α (2.5 ng/mL) and CHX (20 μg/mL) for the indicated times after pretreatment with Z-VAD-FMK (10 μM) for 1 h, and analyzed by immunoblotting with the indicated antibodies. Data are representative of three independent experiments. C, D, G, H HOIL-1L/SHARPIN DKO MEFs stably reconstituted with the indicated proteins were stimulated with TNF-α (2.5 ng/mL) and CHX (20 μg/mL), and cell viability was continuously measured using the xCELLigence system. A representative image (C, G) and statistical analyses of the normalized cell index at 6 h (D, H). Data are shown as the mean ± s.d. of five independent experiments. P values were calculated by a one-way ANOVA with Tukey’s post hoc test. E HOIL-1L/SHARPIN DKO MEFs stably reconstituted with the indicated proteins were stimulated with TNF-α (2.5 ng/mL) and CHX (20 μg/mL) for the indicated times after pretreatment with Z-VAD-FMK (10 μM) for 1 h. Lysates were immunoprecipitated with anti-FADD antibody and immunoblotted as indicated. The experiments were repeated three times, independently, with similar results. Uncropped western blots are available for this figure in the Supplementary Material.