Abstract
The protozoan parasite Plasmodium falciparum, which is responsible for the deadliest form of human malaria, accounts for over half a million deaths a year. These parasites proliferate in human red blood cells by consecutive rounds of closed mitoses called schizogony. Their virulence is attributed to their ability to modify the infected red cells to adhere to the vascular endothelium and to evade immunity through antigenic switches. Spatial dynamics at the nuclear periphery were associated with the regulation of processes that enable the parasites to establish long-term infection. However, our knowledge of components of the nuclear envelope (NE) in Plasmodium remains limited. One of the major protein complexes at the NE is the linker of nucleoskeleton and cytoskeleton (LINC) complex that forms a connecting bridge between the cytoplasm and the nucleus through the interaction of SUN and KASH domain proteins. Here, we have identified two SUN-domain proteins as possible components of the LINC complex of P. falciparum and show that their proper expression is essential for the parasite's proliferation in human red blood cells, and their depletion leads to the formation of membranous whorls and morphological changes of the NE. In addition, their differential expression highlights different functions at the nuclear periphery as PfSUN2 is specifically associated with heterochromatin, while PfSUN1 expression is essential for activation of the DNA damage response. Our data provide indications for the involvement of the LINC complex in crucial biological processes in the intraerythrocytic development cycle of malaria parasites. IMPORTANCE: Plasmodium falciparum, the parasite causing the deadliest form of malaria, is able to thrive in its human host by tight regulation of cellular processes, orchestrating nuclear dynamics with cytoplasmic machineries that are separated by the nuclear envelope. One of the major protein complexes that connect nuclear and cytoplasmic processes in eukaryotes is the linker of nucleoskeleton and cytoskeleton (LINC) complex. However, while the nuclear periphery of P. falciparum was implicated in several important functions, the role of the LINC complex in Plasmodium biology is unknown. Here, we identify two components of P. falciparum LINC complex and demonstrate that they are essential for the parasites' proliferation in human blood, and their depletion leads to the formation of morphological changes in the cell. In addition, the two components have different functions in activating the DNA damage response and in their association with heterochromatin. Our data provide evidence for their essential roles in the parasites' cell cycle.