Summary Epidermal growth factor receptor (EGFR) regulates many crucial cellular programs, with seven different activating ligands shaping cell signaling in distinct ways. Using crystallography and other approaches, we show how the EGFR ligands epiregulin (EREG) and epigen (EPGN) stabilize different dimeric conformations of the EGFR extracellular region. As a consequence, EREG or EPGN induce less stable EGFR dimers than EGF – making them partial agonists of EGFR dimerization. Unexpectedly, this weakened dimerization elicits more sustained EGFR signaling than seen with EGF, provoking responses in breast cancer cells associated with differentiation rather than proliferation. Our results reveal how responses to different EGFR ligands are defined by receptor dimerization strength and signaling dynamics. These findings have broad implications for understanding receptor tyrosine kinase (RTK) signaling specificity. Our results also suggest parallels between partial and/or biased agonism in RTKs and G protein-coupled receptors, as well as new therapeutic opportunities for correcting RTK signaling output.

Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota. In mammals, changes in the composition of the microbiota can influence a wide range of physiologic processes (including development, metabolism, and immune cell function) and are associated with susceptibility to multiple diseases. Alterations in the microbiota can also modulate host behaviors such as social activity, stress, and anxiety-related responses that are linked to diverse neuropsychiatric disorders. However, the mechanisms through which the microbiota influence neuronal activity and host behavior remain poorly defined. Here we demonstrate that manipulation of the microbiota in either antibiotictreated or germ-free adult mice results in significant deficits in fear extinction learning. Single nucleus RNA-sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in multiple cell types including excitatory neurons and glial cells. Transcranial two-photon imaging following deliberate manipulation of the microbiota demonstrated that extinction learning deficits were associated with defective learning-related remodeling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition to effects of manipulating the microbiota on behavior in adult mice, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Lastly, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and were previous reported to be related to human and mouse models of neuropsychiatric disorders, suggesting that microbiota-derived compounds may directly affect brain function and behavior. Together, these data indicate that fear extinction learning requires microbiota-derived signals during both early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.

Retention of Golgi-resident integral membrane proteins depends on the supply of PI(4)P.

Interleukin (IL)-2 is a pleiotropic cytokine that is necessary to prevent chronic inflammation in the gastrointestinal tract 1 – 4 . The protective effects of IL-2 involve the generation, maintenance and function of regulatory T cells (Tregs) 4 – 8 , and low-dose IL-2 has emerged as a potential therapeutic strategy in inflammatory bowel disease (IBD) patients 9 . However, the cellular and molecular pathways that control the production of IL-2 in the context of intestinal health are undefined. Here we identify that IL-2 is acutely required to maintain Tregs and immunologic homeostasis throughout the gastrointestinal tract. Strikingly, lineage-specific deletion of IL-2 in T cells did not recapitulate these phenotypes in the small intestine. Unbiased analyses revealed that group 3 innate lymphoid cells (ILC3) are the dominant cellular source of IL-2 in the small intestine, which is selectively induced by IL-1β. Macrophages produce IL-1β in the small intestine and activation of this pathway involves MyD88- and Nod2-dependent sensing of the microbiota. Loss-of-function studies defined that ILC3-derived IL-2 is essential to maintain Tregs, immunologic homeostasis and oral tolerance to dietary antigens uniquely in the small intestine. Furthermore, ILC3 production of IL-2 was significantly reduced in the small intestine of Crohn’s disease patients, and this correlated with diminished Tregs. Collectively, these results reveal a previously unappreciated pathway whereby a microbiota- and IL-1β-dependent axis promotes ILC3 production of IL-2 to orchestrate immune regulation in the intestine.

No abstract