Abstract
The cGAS–STING pathway is a key component of the innate immune system and exerts crucial roles in the detection of cytosolic DNA and invading pathogens. Accumulating evidence suggests that the intrinsic cGAS–STING pathway not only facilitates the production of type I interferons (IFN-I) and inflammatory responses but also triggers autophagy. Autophagy is a homeostatic process that exerts multiple effects on innate immunity. However, systematic evidence linking the cGAS–STING pathway and autophagy is still lacking. Therefore, one goal of this review is to summarize the known mechanisms of autophagy induced by the cGAS–STING pathway and their consequences. The cGAS–STING pathway can trigger canonical autophagy through liquid-phase separation of the cGAS–DNA complex, interaction of cGAS and Beclin-1, and STING-triggered ER stress–mTOR signaling. Furthermore, both cGAS and STING can induce non-canonical autophagy via LC3-interacting regions and binding with LC3. Subsequently, autophagy induced by the cGAS–STING pathway plays crucial roles in balancing innate immune responses, maintaining intracellular environmental homeostasis, alleviating liver injury, and limiting tumor growth and transformation.
Highlights
Pattern recognition receptors (PRRs) serve as innate immune sensors of danger signals, including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activate the cellular stress response [1]
6 Autophagy induced by the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway is crucial for the modulation of innate immune responses, to maintain intracellular environmental homeostasis, to protect against liver injuries, and to limit cellular transformation and tumor growth
Autophagy induced by the cGAS–STING pathway is crucial for balancing innate immune responses, maintaining intracellular environmental homeostasis, preventing liver injury, and limiting tumor growth and transformation
Summary
Pattern recognition receptors (PRRs) serve as innate immune sensors of danger signals, including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activate the cellular stress response [1]. The cGAS–STING pathway, comprising the cyclic GMP–AMP synthase (cGAS) and the stimulator of interferon genes (STING), was discovered as an important DNA-sensing machinery in innate immunity and pathogenic defense [3,4,5]. STING from the sea anemone (Nematostella vectensis) induces autophagy but not interferon in response to stimulation by cGAMP, which suggests that autophagy is a primordial function of the cGAS–STING pathway [8]. Several studies have provided evidence showing that autophagy could be induced by cGAS directly without any involvement of STING during DNA virus infections [15,16]. The cGAS–STING signaling pathway induces type I IFN and inflammatory signaling responses and activates other cellular processes including autophagy and apoptosis
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