SIP2 is the master transcription factor of Plasmodium merozoite formation.

Malaria, one of the most serious infectious diseases worldwide, is caused by the proliferation of Plasmodium parasites through repeated cycles of intraerythrocytic development. The parasite replicates via schizogony in host erythrocytes, producing multiple progeny merozoites that invade new erythrocytes. Although merozoite formation is the most crucial step in malaria pathogenesis, its molecular mechanism remains unclear. SIP2 is an AP2 transcription factor expressed during schizogony and is particularly conserved among erythrocyte-infecting apicomplexan parasites. Here, we reveal that SIP2 in Plasmodium berghei (PbSIP2) functions as the master transcription factor for merozoite formation. Conditional disruption of pbsip2 resulted in developmental arrest before merozoite formation and notable down-regulation of merozoite-related genes. ChIP-seq showed that PbSIP2 comprehensively activated merozoite-related genes by binding to previously reported cis-regulatory elements of merozoite invasion-related genes, including the bipartite motif (TGCAN4-6GTGCA). Collectively, our results indicate that SIP2 is a transcription factor that establishes erythrocyte infectivity and may have an evolutionary origin from the common ancestor of erythrocyte-infecting apicomplexan parasites.