ROP16 of Toxoplasma gondii Inhibits Innate Immunity by Triggering cGAS-STING Pathway Inactivity through the Polyubiquitination of STING

Abstract

cGAS-STING signaling is a major pathway in inducing type Ⅰ IFN, which plays a crucial role in the defense against T. gondii infection. In contrast, T. gondii develops multiple strategies to counteract the host defense, causing serious diseases in a wide range of hosts. Here, we demonstrate that T. gondii rhoptry protein 16 (ROP16) dampens type I interferon signaling via the inhibition of the cGAS (cyclic GMP-AMP synthase) pathway through the polyubiquitination of STING. Mechanistically, ROP16 interacts with STING through the SignalP domain and inhibits the K63-linked ubiquitination of STING in an NLS (nuclear localization signal)-domain-dependent manner. Consequently, knocking out the ROP16 in PRU tachyzoites promotes the STING-mediated production of type I IFNs and limits the replication of T. gondii. Together, these findings describe a distinct pathway where T. gondii exploits the ubiquitination of STING to evade host anti-parasite immunity, revealing new insights into the interaction between the host and parasites.

Toxoplasma gondii suppresses proliferation and migration of breast cancer cells by regulating their transcriptome

“…ROP16 can polyubiquitinate STING, resulting in inactivate cGAS-STING signaling pathway [ 54 ]. In this way, STING was inactivated and subsequently decreased the secretion of inflammatory cytokines, downregulating the STAT1 and NF-κB pathways in brain metastatic cells, thereby suppressing the brain metastasis of breast cancer and lung cancer [ 55 , 56 ].…”

Mutual regulations between Toxoplasma gondii and type I interferon

“…Whether other effector molecules of T. gondii also play a negative regulatory role in the stage of co-infection needs to be considered and further studied. Recently, research reported that ROP16 II diminished IFN-I signaling, which independent on its kinase activity, via the inhibition of the cGAS pathway by suppressing K63-linked ubiquitination of STING ( Figure 2 ) ( 70 ). However, the dense granule protein 15 (GRA15 II ), another protein from T. gondii , promotes STING polyubiquitination at Lys-337 and STING oligomerization through a TRAF protein–dependent process, and subsequently enhances the host DNA/cGAS/STING pathway against T. gondii infection ( Figure 2 ) ( 71 ).…”