Fei Wang

Bio: Fei Wang is an academic researcher from Tongji University. The author has contributed to research in topics: Medicine & Innate immune system. The author has an hindex of 3, co-authored 8 publications receiving 82 citations.

MicroRNA-27a controls the intracellular survival of Mycobacterium tuberculosis by regulating calcium-associated autophagy

Abstract: Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) kills millions every year, and there is urgent need to develop novel anti-TB agents due to the fast-growing of drug-resistant TB. Although autophagy regulates the intracellular survival of Mtb, the role of calcium (Ca2+) signaling in modulating autophagy during Mtb infection remains largely unknown. Here, we show that microRNA miR-27a is abundantly expressed in active TB patients, Mtb-infected mice and macrophages. The target of miR-27a is the ER-located Ca2+ transporter CACNA2D3. Targeting of this transporter leads to the downregulation of Ca2+ signaling, thus inhibiting autophagosome formation and promoting the intracellular survival of Mtb. Mice lacking of miR-27a and mice treated with an antagomir to miR-27a are more resistant to Mtb infection. Our findings reveal a strategy for Mtb to increase intracellular survival by manipulating the Ca2+-associated autophagy, and may also support the development of host-directed anti-TB therapeutic approaches.

cGAS facilitates sensing of extracellular cyclic dinucleotides to activate innate immunity

Abstract: Cyclic dinucleotides (CDNs) are important second messenger molecules in prokaryotes and eukaryotes. Within host cells, cytosolic CDNs are detected by STING and alert the host by activating innate immunity characterized by type I interferon (IFN) responses. Extracellular bacteria and dying cells can release CDNs, but sensing of extracellular CDNs (eCDNs) by mammalian cells remains elusive. Here, we report that endocytosis facilitates internalization of eCDNs. The DNA sensor cGAS facilitates sensing of endocytosed CDNs, their perinuclear accumulation, and subsequent STING-dependent release of type I IFN Internalized CDNs bind cGAS directly, leading to its dimerization, and the formation of a cGAS/STING complex, which may activate downstream signaling. Thus, eCDNs comprise microbe- and danger-associated molecular patterns that contribute to host-microbe crosstalk during health and disease.

CGAS is a micronucleophagy receptor for the clearance of micronuclei

Abstract: Micronuclei are constantly considered as a marker of genome instability and very recently found to be a trigger of innate immune responses. An increased frequency of micronuclei is associated with ...

PLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1

Abstract: Excessive or uncontrolled release of proinflammatory cytokines caused by severe viral infections often results in host tissue injury or even death. Phospholipase C (PLC)s degrade phosphatidylinositol-4, 5-bisphosphate (PI(4,5)P2) lipids and regulate multiple cellular events. Here, we report that PLCβ2 inhibits the virus-induced expression of pro-inflammatory cytokines by interacting with and inhibiting transforming growth factor-β-activated kinase 1 (TAK1) activation. Mechanistically, PI(4,5)P2 lipids directly interact with TAK1 at W241 and N245, and promote its activation. Impairing of PI(4,5)P2’s binding affinity or mutation of PIP2-binding sites on TAK1 abolish its activation and the subsequent production of pro-inflammatory cytokines. Moreover, PLCβ2-deficient mice exhibit increased expression of proinflammatory cytokines and a higher frequency of death in response to virus infection, while the PLCβ2 activator, m-3M3FBS, protects mice from severe Coxsackie virus A 16 (CVA16) infection. Thus, our findings suggest that PLCβ2 negatively regulates virus-induced pro-inflammatory responses by inhibiting phosphoinositide-mediated activation of TAK1. Phospholipase C β (PLCβ) exhibits immuno-modulatory functions but its role in antiviral innate responses is unclear. Here, the authors provide evidence that PLCβ2 down regulates enterovirus-induced pro-inflammatory responses via inhibition of TAK1 activation, and suggest PLC as a potential therapeutic target.

Molecular mechanisms and cellular functions of cGAS–STING signalling

Abstract: The cGAS–STING signalling axis, comprising the synthase for the second messenger cyclic GMP–AMP (cGAS) and the cyclic GMP–AMP receptor stimulator of interferon genes (STING), detects pathogenic DNA to trigger an innate immune reaction involving a strong type I interferon response against microbial infections. Notably however, besides sensing microbial DNA, the DNA sensor cGAS can also be activated by endogenous DNA, including extranuclear chromatin resulting from genotoxic stress and DNA released from mitochondria, placing cGAS–STING as an important axis in autoimmunity, sterile inflammatory responses and cellular senescence. Initial models assumed that co-localization of cGAS and DNA in the cytosol defines the specificity of the pathway for non-self, but recent work revealed that cGAS is also present in the nucleus and at the plasma membrane, and such subcellular compartmentalization was linked to signalling specificity of cGAS. Further confounding the simple view of cGAS–STING signalling as a response mechanism to infectious agents, both cGAS and STING were shown to have additional functions, independent of interferon response. These involve non-catalytic roles of cGAS in regulating DNA repair and signalling via STING to NF-κB and MAPK as well as STING-mediated induction of autophagy and lysosome-dependent cell death. We have also learnt that cGAS dimers can multimerize and undergo liquid–liquid phase separation to form biomolecular condensates that could importantly regulate cGAS activation. Here, we review the molecular mechanisms and cellular functions underlying cGAS–STING activation and signalling, particularly highlighting the newly emerging diversity of this signalling pathway and discussing how the specificity towards normal, damage-induced and infection-associated DNA could be achieved. The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway senses DNA in the cytoplasm, whether of pathogenic or endogenous (chromatin or mitochondrial) origin, and triggers the interferon response. The mechanisms of DNA recognition and cGAS–STING activation and signalling are now coming into focus, providing insights into the cellular functions of this pathway, including interferon-independent roles.

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response.

Abstract: Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immune-surveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

New insights into the evasion of host innate immunity by Mycobacterium tuberculosis

Abstract: Mycobacterium tuberculosis (Mtb) is an extremely successful intracellular pathogen that causes tuberculosis (TB), which remains the leading infectious cause of human death. The early interactions between Mtb and the host innate immune system largely determine the establishment of TB infection and disease development. Upon infection, host cells detect Mtb through a set of innate immune receptors and launch a range of cellular innate immune events. However, these innate defense mechanisms are extensively modulated by Mtb to avoid host immune clearance. In this review, we describe the emerging role of cytosolic nucleic acid-sensing pathways at the host–Mtb interface and summarize recently revealed mechanisms by which Mtb circumvents host cellular innate immune strategies such as membrane trafficking and integrity, cell death and autophagy. In addition, we discuss the newly elucidated strategies by which Mtb manipulates the host molecular regulatory machinery of innate immunity, including the intranuclear regulatory machinery, the ubiquitin system, and cellular intrinsic immune components. A better understanding of innate immune evasion mechanisms adopted by Mtb will provide new insights into TB pathogenesis and contribute to the development of more effective TB vaccines and therapies.

Gasdermin D in macrophages restrains colitis by controlling cGAS-mediated inflammation.

Abstract: The functional relevance and mechanistic basis of the effects of the pyroptosis executioner Gasdermin D (GSDMD) on colitis remain unclear. In this study, we observed that GSDMD protein was activated during intestinal inflammation in a model of chemically induced colitis. GSDMD deficiency exacerbated experimental colitis independent of changes in the microbiota and without affecting the production of antimicrobial peptides. GSDMD deficiency in macrophages, but not epithelial cells, was sufficient to drive this exacerbated experimental colitis. We further demonstrate that GSDMD functions in macrophages as a negative regulator to control cyclic GMP–AMP synthase (cGAS)–dependent inflammation, thereby protecting against colitis. Moreover, the administration of cGAS inhibitor can rescue the colitogenic phenotype in GSDMD-deficient mice. Collectively, these findings provide the first demonstration of GSDMD’s role in controlling colitis and a detailed delineation of the underlying mechanism.