Endoplasmic reticulum localized TMEM33 domain-containing protein is crucial for all life cycle stages of the malaria parasite.

Endoplasmic reticulum (ER) plays a pivotal role in the regulation of stress responses in multiple eukaryotic cells. However, little is known about the effector mechanisms that regulate stress responses in ER of the malaria parasite. Herein, we aimed to identify the importance of a transmembrane protein 33 (TMEM33)-domain-containing protein in life cycle of the rodent malaria parasite Plasmodium berghei. TMEM33 is an ER membrane-resident protein that is involved in regulating stress responses in various eukaryotic cells. A C-terminal tagged TMEM33 was localized in the ER throughout the blood and mosquito stages of development. Targeted deletion of TMEM33 confirmed its importance for asexual blood stages and ookinete development, in addition to its essential role for sporozoite infectivity in the mammalian host. Pilot scale analysis shows that the loss of TMEM33 results in the initiation of ER stress response and induction of autophagy. Our findings conclude an important role of TMEM33 in the development of all life cycle stages of the malaria parasite, which indicates its potential as an antimalarial target.