1. Cutting Edge in IFN Regulation: Inflammatory Caspases Cleave cGAS
Simon Heidegger, Tobias Haas, Hendrik Poeck 
Immunity 
Volume 46, Issue 3, Pages (March 2017)
DOI: /j.immuni
Copyright © 2017 Elsevier Inc. Terms and Conditions

2. Figure 1
Inflammatory Caspases Cleave the Cytosolic DNA Sensor cGAS to Limit the Release of Type I Interferon
Upon binding of cytosolic double-stranded (ds) DNA, cyclic GMP-AMP synthetase (cGAS) produces the second messenger cyclic GMP-AMP (cGAMP) to activate the adaptor protein stimulator of interferon genes (STING). STING signals via TANK-binding kinase 1 (TBK1) to recruit the transcription factor interferon-regulatory factor 3 (IRF3) for potent type I IFN (IFN-I) release. Concurrent binding of cytosolic dsDNA by absent in melanoma 2 (AIM2) results in the formation of an apoptosis-associated speck-like protein containing a CARD domain (ASC)-containing inflammasome that activates caspase-1. Caspase-1 processes pro-IL-1β to its mature form and can potentially drive a lytic type of cell death called “pyroptosis.” Aberrant cytosolic RNA (e.g., 5′-triphosphorylated RNA, 3p-RNA) can be detected by retinoic acid inducible gene I (RIG-I). Signaling through its adaptor mitochondrial antiviral-signaling protein (MAVS) and downstream receptor-interacting serine/threonine-protein kinase 1 (RIPK1), TBK1, and IRF3 results in IFN-I release. Wang et al. (2017) demonstrate that activated caspase-1 cleaves cGAS to limit downstream IFN-I production. Caspase-1 activation was facilitated by either the AIM2 inflammasome or stimuli that trigger formation of the nucleotide-binding domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome, such as liposaccharide (LPS) in combination with adenosine triphosphate (ATP) or rotenone. Caspase-4, -5, and -11, activated during non-canonical inflammasome formation in response to cytosolic LPS delivery, were also found to cleave cGAS.
Immunity  , DOI: ( /j.immuni )
Copyright © 2017 Elsevier Inc. Terms and Conditions