| Summary: | cGAS-STING signaling is a major pathway in inducing type Ⅰ IFN, which plays a crucial role in the defense against <i>T. gondii</i> infection. In contrast, <i>T. gondii</i> develops multiple strategies to counteract the host defense, causing serious diseases in a wide range of hosts. Here, we demonstrate that <i>T. gondii</i> 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 <i>T. gondii.</i> Together, these findings describe a distinct pathway where <i>T. gondii</i> exploits the ubiquitination of STING to evade host anti-parasite immunity, revealing new insights into the interaction between the host and parasites.
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