Crosstalk between the cGAS DNA Sensor and Beclin-1 Autophagy Protein Shapes Innate Antimicrobial Immune Responses

Abstract

Robust immune responses are essential for eliminating pathogens, but must be metered to avoid prolonged immune activation and potential host damage. Upon recognition of microbial DNA, the cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase, or cGAS, produces the second messenger cGAMP to initiate the STING pathway and subsequent interferon (IFN) production. We report that the direct interaction between cGAS and the Beclin-1 autophagy protein not only suppresses cGAMP synthesis to halt IFN production upon double stranded (ds)DNA stimulation or herpes simplex virus-1 infection, but also enhances autophagy-mediated degradation of cytosolic pathogen DNAs to prevent excessive cGAS activation and persistent immune stimulation. Specifically, this interaction releases Rubicon, a negative autophagy regulator, from the Beclin-1 complex, activating phosphatidylinositol 3-kinase class III activity and thereby inducing autophagy to remove cytosolic pathogen DNAs. Thus, the cGAS-Beclin-1 interaction shapes innate immune responses by regulating both cGAMP production and autophagy, resulting in well-balanced anti-microbial immune responses.

TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity

“…One aspect of this role of autophagy is regulation of inflammasome activity (Schroder and Tschopp, 2010), whereby autophagy antagonizes inflammasome activation, through several proposed mechanisms (Saitoh et al, 2008;Nakahira et al, 2011;Zhou et al, 2011;Shi et al, 2012) that are, however, not fully understood. Another distinct manifestation is autophagic suppression of type I IFN responses through STING and RIG-I (retinoic acid-inducible gene 1)-like receptors (Jounai et al, 2007;Saitoh et al, 2009;Tal et al, 2009;Konno et al, 2013;Liang et al, 2014;Deretic et al, 2015). In this work, we show that a subset of TRIMs is involved in selective autophagy of the components of the inflammasome and type I IFN regulatory systems.…”

Autophagy in Pulmonary Diseases

“…ATG9 inhibits the activation of simulator of IFN gene (STING) by inhibiting assembly of STING and TANK-binding kinase I, resulting in the suppression of type I IFN production ( Figure 5C) (25). Beclin 1 suppresses type I IFN response by directly binding to cyclic GMP-AMP synthase in response to viral DNA (26). Autophagy is also critically involved in the adaptive immune system by affecting the functions of T cells, memory B cells, and plasma cells (9,16,17).…”

L’autophagie garante de l’immunité et de l’inflammation

“…De même, ATG9 bloque l'assemblage de STING (stimulator of IFN genes) avec TBK1 (TANK-binding kinase 1) 2 empêchant ainsi la production d'IFN-I en réponse à la présence d'ADN double brin dans le cytosol de la cellule [17]. Enfin, en interagissant avec la cGAMP (cyclic guanosine monophosphate-adenosine monophosphate) synthase cGAS, Beclin-1 (ou ATG6) inhibe l'IFN-I en réponse à de l'ADN viral [18]. L'autophagie régule également l'activation du facteur de transcription NF-B responsable de la synthèse de plusieurs cytokines inflammatoires.…”