Abstract
The cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in host defense by sensing cytosolic DNA derived from microbial pathogens or mis-located cellular DNA. Upon DNA binding, cGAS utilizes GTP and ATP as substrates to synthesize cGAMP, leading to MITA-mediated innate immune response. In this study, we identified the phosphatase PPP6C as a negative regulator of cGAS-mediated innate immune response. PPP6C is constitutively associated with cGAS in un-stimulated cells. DNA virus infection causes rapid disassociation of PPP6C from cGAS, resulting in phosphorylation of human cGAS S435 or mouse cGAS S420 in its catalytic pocket. Mutation of this serine residue of cGAS impairs its ability to synthesize cGAMP upon DNA virus infection. In vitro experiments indicate that S420-phosphorylated mcGAS has higher affinity to GTP and enzymatic activity. PPP6C-deficiency promotes innate immune response to DNA virus in various cells. Our findings suggest that PPP6C-mediated dephosphorylation of a catalytic pocket serine residue of cGAS impairs its substrate binding activity and innate immune response, which provides a mechanism for keeping the DNA sensor cGAS inactive in the absence of infection to avoid autoimmune response.
Highlights
The innate immune system represents the first line of host defense against viral infection
Our findings suggest that PPP6Cmediated dephosphorylation of a catalytic pocket serine residue of cGAS impairs its substrate binding activity and innate immune response, which provides a mechanism for keeping the DNA sensor cGAS inactive in the absence of infection to avoid autoimmune response
We found that protein phosphatase 6 (PPP6C) suppressed phosphorylation of human cGAS at S435 or mouse cGAS at S420 in its substratebinding pocket, preventing its binding to GTP and inhibiting the synthesis of cyclic GMP-AMP (cGAMP)
Summary
The innate immune system represents the first line of host defense against viral infection. Structurally conserved viral components called pathogen associated molecular patterns (PAMPs) are detected by host pattern recognition receptors (PRRs), which triggers intracellular signaling events that lead to induction of type I interferons (IFNs), proinflammatory cytokines and other downstream effectors These downstream effectors inhibit viral replication, facilitate clearance of virus-infected cells, and promote adaptive immune response (Janeway and Medzhitov, 2002; Akira et al, 2006; Hu and Shu, 2018). MITA is translocated from the ER via Golgi apparatus to perinuclear punctate structures In this process, MITA recruits TBK1 and IRF3, leading to phosphorylation and activation of IRF3, induction of PPP6C dephosphorylates cGAS downstream antiviral effectors genes, and innate antiviral response (Ishikawa and Barber, 2008; Zhong et al, 2008; Liu et al, 2015). Our findings suggest that PPP6C-mediated dephosphorylation of cGAS impairs its substrate binding activity and innate immune response, which is important to keep cGAS inactive in the absence of infection to avoid autoimmune responses
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
