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

Qi-Wang Jin; Ting Yu; Ming Pan; Yi-Min Fan; Si-Yang Huang

doi:10.3390/cells12141862

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

Cells. 2023 Jul 15;12(14):1862. doi: 10.3390/cells12141862.

Authors

Qi-Wang Jin¹, Ting Yu¹, Ming Pan¹, Yi-Min Fan¹, Si-Yang Huang^{1

2}

Affiliations

¹ Jiangsu Key Laboratory of Zoonosis, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China.
² Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China.

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.

Keywords: ROP16; Toxoplasma gondii; cGAS-STING pathway; immune escape.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Immunity, Innate
Interferon Type I* / metabolism
Membrane Proteins / metabolism
Nucleotidyltransferases / metabolism
Toxoplasma*
Ubiquitination

Substances

Membrane Proteins
Nucleotidyltransferases
Interferon Type I

Grants and funding

This research was funded by the Outstanding Youth Foundation of Jiangsu Province of China, grant number BK20190046; the China Postdoctoral Science Foundation, grant number 2021M702760; and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Veterinary Medicine).