We show that, similar to TCR engagement in vitro, P. yoelii 17XNL can efficiently induce protein neddylation in T cells, abrogation of this process resulted in exacerbated and persistent parasite burdens, leading to a 100% lethality of infection in mice, which seems to be linked to inadequate IFN-γ response and impaired humoral immunity. This evidence concerns the gene IFNG and infection.