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A natural ligand for the orphan receptor GPR15 modulates lymphocyte recruitment to epithelia


GPR15 is an orphan G protein–coupled receptor (GPCR) that is found in lymphocytes. It functions as a co-receptor of simian immunodeficiency virus and HIV-2 and plays a role in the trafficking of T cells to the lamina propria in the colon and to the skin. We describe the purification from porcine colonic tissue extracts of an agonistic ligand for GPR15 and its functional characterization. In humans, this ligand, which we named GPR15L, is encoded by the gene C10ORF99 and has some features similar to the CC family of chemokines. GPR15L was found in some human and mouse epithelia exposed to the environment, such as the colon and skin. In humans, GPR15L was also abundant in the cervix. In skin, GPR15L was readily detected after immunologic challenge and in human disease, for example, in psoriatic lesions. Allotransplantation of skin from Gpr15l-deficient mice onto wild-type mice resulted in substantial graft protection, suggesting nonredundant roles for GPR15 and GPR15L in the generation of effector T cell responses. Together, these data identify a receptor-ligand pair that is required for immune homeostasis at epithelia and whose modulation may represent an alternative approach to treating conditions affecting the skin such as psoriasis.

Regulation of autophagy, NF-{kappa}B signaling, and cell viability by miR-124 in KRAS mutant mesenchymal-like NSCLC cells


KRAS mutant non–small cell lung cancer (NSCLC) may be classified into epithelial or mesenchymal subtypes. Despite having the same "driver" mutation, mesenchymal NSCLCs are less responsive than are epithelial NSCLCs to inhibition of the RAS pathway. Identifying alternative networks that promote survival specifically in mesenchymal NSCLC may lead to more effective treatments for this subtype. Through their numerous targets in cellular signaling pathways, noncoding microRNAs (miRNAs) often function as tumor suppressors or oncogenes. In particular, some miRNAs regulate the epithelial-mesenchymal transition (EMT). We derived an EMT-related miRNA signature by profiling the abundance of miRNAs in a panel of epithelial (KE) or mesenchymal (KM) KRAS mutant NSCLC cell lines. This signature revealed a number of suppressed miRNAs in KM cell lines, including members of the miR-200 family, which can suppress tumor progression by inhibiting EMT. Reconstituting KM cells with one of these miRNAs, miR-124, disrupted autophagy and decreased cell survival by reducing the abundance of p62, which is both an adaptor for selective autophagy and a regulator of the transcription factor nuclear factor B (NF-B). Suppression of p62 by miR-124 correlated with reduced abundance of the autophagy activator beclin 1 (BECN1), the ubiquitin ligase TRAF6, and the NF-B subunit RELA/p65. The abundance of miR-124 inversely correlated with the expression of BECN1 and TRAF6 in patient NSCLC samples. These findings reveal how the loss of miR-124 promotes cell survival networks in the aggressive mesenchymal subtype of KRAS mutant NSCLC, which might lead to improved subtype-selective therapeutic strategies for patients.

Papers of note in Science 357 (6355)


This week’s articles describe an alternative mechanism of secretion that is deployed by intestinal cells in the presence of pathogens; how the immune system protects the lungs from inhaled fungal spores; and metabolic reprogramming of tissue-resident antigen-presenting cells in the lung.

Papers of note in Nature 549 (7670)


This week’s articles identify microbial metabolites that stimulate GPCRs; a transmembrane protein that maintains PD-L1 at the plasma membrane; immune enhancer elements that respond to specific extracellular signals; a signaling pathway that defines the right side of the vertebrate embryo; functions for ionotropic glutamate receptors in plants; and structural features of AMPA receptors during activation and desensitization.

Leaky nuclei lead to senescence


A pathway that senses microbial DNA also promotes senescence in cells with cytosolic chromatin fragments.

Chemotherapy, pain, and gut microbiota


Chemotherapy triggers gut microbiota to stimulate pain-associated peripheral inflammation.

Paper of note in Science Translational Medicine 9 (406)


This week’s article describes how targeted antimicrobials may reduce the virulence of Clostridium difficile infection.