Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP

Andrea Ablasser, Jonathan L. Schmid-Burgk, Inga Hemmerling, Gabor L. Horvath, Tobias Schmidt, Eicke Latz, & Veit Hornung. Nature. (2013) 503, 530-534

Speaker: Cheng-Lun Hsu (徐政倫)                      Time: 14:00~15:00, Mar. 19, 2014

Commentator: Dr. Pei-Jane Tsai (蔡佩珍)           Place: Room 601

Abstract:

The cellular collaboration is required for innate immune defense of metazoan against microbial pathogens. Intercellular information exchange, which alarms the host innate immune system to defend pathogen invasion, is generally attributed to cytokines and chemokines secreted by pathogen-infected cells. Cytokines like type I interferons (IFNs) function to alert the non-infected cells to the possibility of virus challenge. Many cytosolic sensors for viral nucleic acids link to the induction of antiviral type I IFNs . Among these cytosolic sensors, cyclic GMP-AMP (cGAMP) synthase (cGAS) is a newly identified DNA sensor, which catalyses the synthesis of second messenger cGAMP (2'-5') upon sensing viral DNA (1, 2). The molecule cGAMP (2'-5') directly binds to the ER-resident adaptor STING, thereby activating the secretion of type I IFNs (2). However, whether and how cGAMP (2'-5') acts as a second messenger to alarm non-infected cells for defending virus infection remains unclear. Here this report demonstrates that cGAMP (2'-5') is transferred from producing cells to neighboring cells through gap junctions, where it promotes bystander STING activation and antiviral immunity. Gap junction allowing specific small messenger cGAMP (2'-5') to pass is essential for conveying this bystander immunity. The decrease in bystander STING activation and IRF3 phosphorylation is shown in blockage of gap junction by using the inhibitor or genetic approach. Furthermore, this phenomenon which is also observed in vaccinia virus-infected cells suggests its physiological relevance. Taken together, cGAS-triggered intercellular transfer of cGAMP (2'-5') might provide the host a novel strategy of mounting antiviral immunity in metazoan. .

References:

1.     Lijun Sun. et al. (2013) Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway. Science 339, 786-791.

2.    Jiaxi Wu. et al. (2013) Cyclic GMP-AMP Is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA. Science 339, 826-830.