News & Events
Spotlight on Innate Immune Science: cGAS-STING’s Role in Human SLE; Cryo-EM Structures of Full-length NLRP3; cGAS- and cGAMP-independent Mode of STING Activation in Niemann–Pick disease type C
In this series, our team of biologists and scientific advisors breaks down the latest research and trends in innate immune system science from leading publications and institutions.
Aberrant accumulation of mitochondria in red blood cells leads to activation of the c-GAS-STING pathway in human lupus patients
Summary: A paper published in Cell shows that programmed mitochondrial removal, a hallmark of mammalian erythropoiesis, is defective in a subset of patients with systemic lupus erythematosus (SLE). Researchers demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor (HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasome system (UPS), which precedes and is necessary for the autophagic removal of mitochondria. Interestingly, a subgroup of SLE patients fail to engage HIF-regulated metabolic and proteasomal pathways, causing the accumulation of abnormal, mitochondria-containing red blood cells. Macrophages engulf these cells, and the RBC mitochondrial DNA activates cGAS-STING-dependent inflammation.
The cGAS-STING pathway is a key cellular sensor of cytosolic double-stranded DNA (dsDNA), allowing the innate immune system to detect pathogens. Antibody-mediated internalization of abnormal red blood cells (RBCs) carrying mitochondria (Mito+ RBCs) by macrophages results in accumulation of mitochondrial DNA from these engulfed RBCs, which in turn induces type I interferon (IFN) production through activation of the cGAS/STING pathway. Indeed, SLE patients carrying both Mito+ RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulated gene (ISG) signatures, a distinctive feature of SLE.
So What: The results of this study are consistent with evidence linking mitochondrial dysfunction to SLE pathogenesis, and point to a potential precision medicine approach toward identifying patients whose disease is being driven by accumulation of mitochondria-containing RBCs that trigger abnormal activation of the cGAS-STING pathway.
Cryo-EM studies show that ADP-bound NLRP3 is a decamer composed of a pentamer of dimers
Summary: NLRP3 is an intracellular sensor protein whose activation by a broad spectrum of exogenous and endogenous stimuli leads to inflammasome formation, the production of pro-inflammatory mediators like IL-1β and IL-18 and pyroptosis.
IFM Co-founders and Scientific Advisors Eicke Latz, MD, PhD, Matthias Geyer, PhD, and colleagues showed through cryogenic electron microscopy (cryo-EM) that ADP-bound NLRP3 forms a decamer composed of a pentamer of dimers. In a pre-print manuscript available on bioRxiv, the authors reported the cryo-EM structures of full-length NLRP3 in its native form and in complex with anti-inflammatory agent and NLRP3 antagonist CRID3.
In its inactive form, ADP-bound NLRP3 is a decamer composed of five homodimers, where the leucine-rich repeat (LRR) domains in each homodimer assemble back-to-back as a pentamer, overall forming a spherical structure. The NACHT domain, which contains the ATP binding site, is located at the apical axis of this sphere. The acidic loop of the LRR domain binds the concave side of the LRR, mediating contacts to an opposing LRR chain. CRID3 binding stabilizes the decamer by connecting four subdomains in the NACHT and LRR domains and thus prevent conformational changes in the complex necessary for function. The central sulfonylurea group of CRID3 interacts with two arginines from opposite sides of the nucleotide-binding site’s Walker A motif, explaining its specificity for NLRP3. The structure of this complex differs in certain significant ways from the previously published NLRP3-NEK7 complex.
So What: NLRP3 activation is involved in numerous inflammatory diseases, including cryopyrin-associated periodic syndromes (CAPS), osteoarthritis, Crohn’s disease, gout, cardiovascular disease, hepatic and pulmonary fibrosis, and non-alcoholic steatohepatitis. NLRP3 inhibitors ‒ some of which are in clinical trials, including one developed by IFM and acquired by Novartis ‒ could become important drugs for treating this variety of diseases that all have an underlying inflammatory driver of NLRP3 activity. Understanding of the three-dimensional NLRP3 structure helps explain the activity and selectivity of current NLRP3 antagonists and could aid in the development of new molecules.
STING signalling contributes to the pathology in Niemann–Pick disease type C independent of cGAS- and cGAMP
Summary: Scientists at the University of Texas Southwestern Medical Center in Dallas, Texas, uncovered a cGAS- and cGAMP-independent mode of STING activation as the driver of Niemann–Pick disease type C (NPC1). Their mechanistic findings on the neuropathology in Npc1 KO mice validate STING as therapeutic target for the treatment of NPC1.
This study revealed that NPC1 interacts with STING and recruits it to the lysosome for degradation. The scientists also found that Npc1 deficiency ‘primes’ STING signaling by tethering STING to SREBP2 trafficking. Loss of NPC1 protein then ‘boosts’ STING signaling by blocking its lysosomal degradation. Both priming and boosting of STING signalling are required for the severe neurological disease observed in Npc1−/− mice. Genetic deletion of Sting1 (the gene that encodes STING), but not the removal of Cgas, significantly reduced the activation of microglia and relieved the loss of Purkinje neurons in the cerebellum of Npc1−/− mice, leading to improved motor function. In addition, STING antagonists reduce type 1 interferon pathway activation in cells from the Npc1−/− mice.
So What: This study describes a novel mechanism by which loss of NPC1 results in chronic STING activation without the involvement of cGAS. The resulting STING-driven inflammation is responsible for severe neurological disease, which points to the possibility that pharmacologically blocking STING signalling could provide a therapeutic avenue for treating patients with Niemann-Pick disease type C.
Stay tuned for additional studies and perspectives shared by the IFM R&D Team!