Toxoplasma gondii UBL-UBA shuttle proteins regulate several important cellular processes.

Heng Zhang, Yangfei Xue, Xu Yang, Jing Liu, Qun Liu

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2021 Dec

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Toxoplasma gondii is an obligate intracellular apicomplexan parasite causing lethal diseases in immunocompromised patients. UBL-UBA shuttle proteins (DDI1, RAD23, and DSK2) are important components of the ubiquitin-proteasome system. By degrading ubiquitinated proteins, UBL-UBA shuttle proteins regulate many cellular processes. However, the specific processes regulated by UBL-UBA shuttle proteins remain elusive. Here, we revealed that the deletion of shuttle proteins results in a selective accumulation of ubiquitinated proteins in the nucleus and aberrant DNA replication. ROP18 was mistargeted and accumulated in the shuttle protein mutant strain, resulting in the recruitment of immunity-related GTPases to the parasitophorous vacuole membrane (PVM). Furthermore, the mistargeting of ROP18 and the recruitment of Irgb6 to the PVM were also observed in the DDI1 mutant strain. DDI1 is a nonclassical UBL-UBA shuttle protein homologous to the HIV-1 protease. Molecular docking showed that DDI1 was a potential target of HIV-1 protease inhibitors. However, these inhibitors blocked the growth of T gondii in vitro but not in vivo. In conclusion, the Toxoplasma UBL-UBA shuttle protein regulates several important cellular processes and the mistargeting of ROP18 may be a representative of the abnormal homeostasis caused by shuttle protein mutation. © 2021 Federation of American Societies for Experimental Biology.

Citation

Heng Zhang, Yangfei Xue, Xu Yang, Jing Liu, Qun Liu. Toxoplasma gondii UBL-UBA shuttle proteins regulate several important cellular processes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2021 Dec;35(12):e21898