Toxoplasma and other Apicomplexan parasites, switch between different developmental stages to persist in and transmit between hosts. Toxoplasma can alternate between systemic tachyzoites and encysted bradyzoite forms found in the CNS and muscle tissues. How parasites sense these tissue types and trigger differentiation remains largely unknown. We show that Toxoplasma differentiation into latent forms is induced under metabolic conditions that mimic CNS and muscle tissue and using a series of in vitro and in vivo CRISPR screen identify parasite genes required for this process. From ~25 genes we find as being important for differentiation we find almost every component of a E3 ubiquitin ligase complex orthologous to the glucose induced degradation deficient (GID) complex in yeast and CTLH complex in humans. We show that the makeup of this complex and show that it is localised in the cytoplasm and nucleus of Toxoplasma. We show that TgGID likely regulates translational repression of a key transcription factor required for differentiation, BFD1, through its 3’ utr. Overall, this work provides important new insight into how these divergent parasites sense different host cell niches and trigger stage conversion through a ubiquitination-dependent program.