Bacterial quorum-sensing autoinducers are small chemicals released to control microbial community behaviours. N -(3-oxo-dodecanoyl) homoserine lactone, the autoinducer of the Pseudomonas aeruginosa LasI–LasR circuitry, triggers significant cell death in lymphocytes. We found that this molecule is incorporated into the mammalian plasma membrane and induces dissolution of eukaryotic lipid domains. This event expels tumour necrosis factor receptor 1 into the disordered lipid phase for its spontaneous trimerization without its ligand and drives caspase 3–caspase 8-mediated apoptosis. In vivo, P. aeruginosa releases N -(3-oxo-dodecanoyl) homoserine lactone to suppress host immunity for its own better survival; conversely, blockage of caspases strongly reduces the severity of the infection. This work reveals an unknown communication method between microorganisms and the mammalian host and suggests interventions of bacterial infections by intercepting quorum-sensing signalling.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

The NLRP3 inflammasome senses a range of cellular disturbances, although no consensus exists regarding a common mechanism. Canonical NLRP3 activation is blocked by high extracellular K+, regardless of the activating signal. We report here that canonical NLRP3 activation leads to Ca2+ flux and increased calpain activity. Activated calpain releases a pool of Caspase-1 sequestered by the cytoskeleton to regulate NLRP3 activation. Using electrophysiological recording, we found that resting-state eukaryotic membrane potential (MP) is required for this calpain activity, and depolarization by high extracellular K+ or artificial hyperpolarization results in the inhibition of calpain. Therefore, the MP/Ca2+/calpain/Caspase-1 axis acts as an independent regulatory mechanism for NLRP3 activity. This finding provides mechanistic insight into high K+-mediated inhibition of NLRP3 activation, and it offers an alternative model of NLRP3 inflammasome activation that does not involve K+ efflux.

Phagocytosis is one of the earliest cellular functions, developing approximately 2 billion years ago. Although FcR-based phagocytic signaling is well-studied, how it originated from ancient phagocytosis is unknown. Lipid redistribution upregulates a phagocytic program recapitulating FcR-based phagocytosis with complete dependence on Src family kinases, Syk, and phosphoinositide 3-kinases (PI3K). Here we show that in phagocytes, an atypical ITAM sequence in the ancient membrane anchor protein Moesin transduces signal without receptor activation. Plasma membrane deformation created by solid structure binding generates phosphatidylinositol 4,5-bisphosphate (PIP2) accumulation at the contact site, which binds the Moesin FERM domain and relocalizes Syk to the membrane via the ITAM motif. Phylogenic analysis traces this signaling using PI3K and Syk to 0.8 billion years ago, earlier than immune receptor signaling. The proposed general model of solid structure phagocytosis implies a preexisting lipid redistribution-based activation platform collecting intracellular signaling components for the emergence of immune receptors.

[This corrects the article DOI: 10.18632/oncotarget.6461.].

Gastrointestinal commensal microbiota is a concentrated mix of microbial life forms, including bacteria, fungi, archaea and viruses. These life forms are targets of host antimicrobial defense in order to establish a homeostatic symbiosis inside the host. However, they are also instrumental in shaping the functions of our immune system via a diverse set of communication mechanisms. In the gut, T helper 17, regulatory T and B cells are continuously tuned by specific microbial strains and metabolic processes. These cells in return help to establish a mutually beneficial exchange with the gut microbial contents. Imbalances in this symbiosis lead to dysregulations in the host’s ability to control infections and the development of autoimmune diseases. In addition, the commensal microbiota has a significant and obligatory role in shaping both gut intrinsic and distal lymphoid organs, casting a large impact on the overall immune landscape in the host. This review discusses the major components of the microbial community in the gut and how its members collectively and individually exert regulatory roles in the host immune system and lymphoid structure development, as well as the functions of several major immune cell types.

Clinical and experimental preparations of IgG/soluble antigen complexes, as well as those formed following antibody therapy in vivo, are multifaceted immune regulators. These immune complexes (ICs) have been tested in humans and animal models, mostly in forms of experimental or clinical vaccination, for at least a century. With intensified research on Fcγ receptor‐mediated immune modulation, as well as with immune complex‐directed antigen processing, presentation, and inflammatory responses, there are renewed interests of using ICs in vaccines and immunotherapies. Currently, IC‐based immune therapy has been broadly experimented in HBV and HIV viral infection control and antitumor treatments. However, mechanistic insights of IC‐based treatments are relatively recent subjects of study; strong efforts are needed to establish links to connect laboratory findings with clinical practices. This review covers the history, mechanisms, and in vivo outcomes of this safe and effective therapeutic tool, with a clear aim to bridge laboratory findings with evolving clinical applications.

Current guidelines for lung cancer treatment with EGFR tyrosine kinase inhibitors (TKI) include only patients with mutated EGFR, although some patients with wildtype EGFR (wt-EGFR) have exhibited positive responses to this therapy as well. Biomarkers predicting the benefit from EGFR-TKIs treatment remain to be determined for patients with wild-type EGFR.Here, we report that wt-EGFR overexpression transformed cells in vitro and induced tumorigenesis in vivo in transgenic mouse models. Wt-EGFR driven lung cancer was hypersensitive to TKI treatment in mouse model. Lung cancer patients with high-expression of wt-EGFR showed longer Overall Survival in comparison to low-expression patients after TKI treatment. Our data therefore suggest that treatment with EGFR inhibitors should be extended to include not only patients with mutated EGFR but also a subset of patients with overexpression of wt-EGFR.

Transgenic mouse models are widely used in biomedical research; however, current techniques for producing transgenic mice are limited due to the unpredictable nature of transgene expression. Here, we report a novel, highly efficient technique for the generation of transgenic mice with single-copy integration of the transgene and guaranteed expression of the gene-of-interest (GOI). We refer to this technique as f unctionally e nriched ES cell t ransgenics, or FEEST. ES cells harboring an inducible Cre gene enabled the efficient selection of transgenic ES cell clones using hygromycin before Cre-mediated recombination. Expression of the GOI was confirmed by assaying for the GFP after Cre recombination. As a proof-of-principle, we produced a transgenic mouse line containing Cre-activatable tTA (cl-tTA6). This tTA mouse model was able to induce tumor formation when crossed with a transgenic mouse line containing a doxycycline-inducible oncogene. We also showed that the cl-tTA6 mouse is a valuable tool for faithfully recapitulating the clinical course of tumor development. We showed that FEEST can be easily adapted for other genes by preparing a transgenic mouse model of conditionally activatable EGFR L858R. Thus, FEEST is a technique with the potential to generate transgenic mouse models at a genome-wide scale.

The Rac1/JNK cascade plays important roles in DNA damage-induced apoptosis. However, how this cascade is activated upon DNA damage remains to be fully understood. We show here that, in untreated cells, Tiam1, a Rac1-specific guanine nucleotide exchange factor, is phosphorylated by casein kinase 1 (CK1) at its C terminus, leading to Skp, Cullin, F-box-containing(β-TrCP) recognition, ubiquitination, and proteasome-mediated degradation. Upon DNA-damaging anticancer drug treatment, CK1/β-TrCP-mediated Tiam1 degradation is abolished, and the accumulated Tiam1 contributes to downstream activation of Rac1/JNK. Consistently, tumor cells overexpressing Tiam1 are hypersensitive to DNA-damaging drug treatment. In xenograft mice, Tiam1-high cells are more susceptible to doxorubicin treatment. Thus, our results uncover that inhibition of proteasome-mediated Tiam1 degradation is an upstream event leading to Rac1/JNK activation and cell apoptosis in response to DNA-damaging drug treatment.

Peptides presented by MHC class I molecules are mostly derived from proteins synthesized by the antigen‐presenting cell itself, while peptides presented by MHC class II molecules are predominantly from materials acquired by endocytosis. External antigens can also be presented by MHC class I molecules in a process referred to as cross‐presentation. Here, we report that mouse dendritic cell (DC) engagement to a phagocytic target alters endocytic processing and inhibits the proteolytic activities. During phagocytosis, endosome maturation is delayed, shows less progression toward the lysosome, and the endocytosed soluble antigen is targeted for MHC class I cross‐presentation. The antigen processing in these arrested endosomes is under the control of NAPDH oxidase associated ROS. We also show that cathepsin S is responsible for the generation of the MHC class I epitope. Taken together, our results suggest that in addition to solid structure uptake, DC phagocytosis simultaneously modifies the kinetics of endosomal trafficking and maturation. As a consequence, external soluble antigens are targeted into the MHC class I cross‐presentation pathway.