Identifying secreted mediators driving the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in aging or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the exercise benefits on cognitive function. Genetic deletion of FNDC5/irisin (global F5KO mice) impairs cognitive function in exercise, aging, and AD. Diminished pattern separation in F5KOs can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally, and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver, results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of cognitive benefits of exercise and potential therapeutic for treating cognitive disorders including AD.

CD177 is a glycosylphosphatidylinositol (GPI)-anchored protein expressed by a variable proportion of human neutrophils that mediates surface expression of the antineutrophil cytoplasmic antibody antigen proteinase 3. CD177 associates with β2 integrins and recognizes platelet endothelial cell adhesion molecule 1 (PECAM-1), suggesting a role in neutrophil migration. However, CD177 neutrophils exhibit no clear migratory advantage in vivo, despite interruption of in vitro transendothelial migration by CD177 ligation. We sought to understand this paradox. Using a PECAM-1-independent transwell system, we found that CD177 and CD177 neutrophils migrated comparably. CD177 ligation selectively impaired migration of CD177 neutrophils, an effect mediated through immobilization and cellular spreading on the transwell membrane. Correspondingly, CD177 ligation enhanced its interaction with β2 integrins, as revealed by fluorescence lifetime imaging microscopy, leading to integrin-mediated phosphorylation of Src and extracellular signal-regulated kinase (ERK). CD177-driven cell activation enhanced surface β2 integrin expression and affinity, impaired internalization of integrin attachments, and resulted in ERK-mediated attenuation of chemokine signaling. We conclude that CD177 signals in a β2 integrin-dependent manner to orchestrate a set of activation-mediated mechanisms that impair human neutrophil migration.

The Golgi complex plays a central role in the intracellular sorting of secretory proteins 1,2. Anterograde transport through the Golgi has been explained by the movement of Golgi cisternae, known as cisternal maturation 3–5. Because this explanation is now appreciated to be incomplete 6, interest has developed in understanding tubules that connect the Golgi cisternae 7–9. Here, we find that the Coat Protein I (COPI) complex sorts anterograde cargoes into these tubules. Moreover, the small GTPase cdc42 regulates bidirectional Golgi transport by targeting the dual functions of COPI in cargo sorting and carrier formation. Cdc42 also directly imparts membrane curvature in promoting COPI tubule formation. Our findings further reveal that COPI tubular transport complements cisternal maturation in explaining how anterograde Golgi transport is achieved, and that bidirectional COPI transport is modulated by environmental cues through cdc42.

CD47 plays an important but incompletely understood role in innate and adaptive immune responses. CD47 associates in cis with T-cell LFA-1 integrins and regulates expression of high-affinity conformations of both LFA-1 and VLA-4.

Metabolic studies suggest that the absorptive capacity of the small intestine for fructose is limited, though the molecular mechanisms controlling this process remain unknown. Here we demonstrate that thioredoxin-interacting protein (Txnip), which regulates glucose homeostasis in mammals, binds to fructose transporters and promotes fructose absorption by the small intestine. Deletion of Txnip in mice reduced fructose transport into the peripheral bloodstream and liver, as well as the severity of adverse metabolic outcomes resulting from long-term fructose consumption. We also demonstrate that fructose consumption induces expression of Txnip in the small intestine. Diabetic mice had increased expression of Txnip in the small intestine as well as enhanced fructose uptake and transport into the hepatic portal circulation. The deletion of Txnip in mice abolished the diabetes-induced increase in fructose absorption. Our results indicate that Txnip is a critical regulator of fructose metabolism and suggest that a diabetic state can promote fructose uptake.DOI: http://dx.doi.org/10.7554/eLife.18313.001

Antibody ligation of the murine neutrophil surface protein Ly6G disrupts neutrophil migration in some contexts but not others. We tested whether this variability reflected divergent dependence of neutrophil migration on β2 integrins, adhesion molecules that interact with Ly6G at the neutrophil surface. In integrin-dependent murine arthritis, Ly6G ligation attenuated joint inflammation, even though mice lacking Ly6G altogether developed arthritis normally. By contrast, Ly6G ligation had no impact on integrin-independent neutrophil migration into inflamed lung. In peritoneum, the role of β2 integrins varied with stimulus, proving dispensable for neutrophil entry in Escherichia coli peritonitis but contributory in interleukin 1 (IL-1)–mediated sterile peritonitis. Correspondingly, Ly6G ligation attenuated only IL-1 peritonitis, disrupting the molecular association between integrins and Ly6G and inducing cell-intrinsic blockade restricted to integrin-dependent migration. Consistent with this observation, Ly6G ligation impaired integrin-mediated postadhesion strengthening for neutrophils arresting on activated cremaster endothelium in vivo. Together, these findings identify selective inhibition of integrin-mediated neutrophil emigration through Ly6G ligation, highlighting the marked site and stimulus specificity of β2 integrin dependence in neutrophil migration.

The initial steps in the synthesis of leukotrienes are the translocation of 5-lipoxygenase (5-LO) to the nuclear envelope and its subsequent association with its scaffold protein 5-lipoxygenase-activating protein (FLAP). A major gap in our understanding of this process is the knowledge of how the organization of 5-LO and FLAP on the nuclear envelope regulates leukotriene synthesis. We combined single molecule localization microscopy with Clus-DoC cluster analysis, and also a novel unbiased cluster analysis to analyze changes in the relationships between 5-LO and FLAP in response to activation of RBL-2H3 cells to generate leukotriene C4. We identified the time-dependent reorganization of both 5-LO and FLAP into higher-order assemblies or clusters in response to cell activation via the IgE receptor. Clus-DoC analysis identified a subset of these clusters with a high degree of interaction between 5-LO and FLAP that specifically correlates with the time course of LTC4 synthesis, strongly suggesting their role in the initiation of leukotriene biosynthesis.

1The initial steps in the synthesis of leukotrienes are the translocation of 5-lipoxygenase 2 (5-LO) to the nuclear envelope and its subsequent association with its scaffold protein 5-3 lipoxygenase-activating protein (FLAP). A major gap in our understanding of this process is the 4 knowledge of how the organization of 5-LO and FLAP on the nuclear envelope regulates 5 leukotriene synthesis. We combined single molecule localization microscopy with Clus-DoC 6 cluster analysis, and also a novel unbiased cluster analysis to analyze changes in the 7 relationships between 5-LO and FLAP in response to activation of RBL-2H3 cells to generate 8 leukotriene C 4 . We identified the time-dependent reorganization of both 5-LO and FLAP into 9 higher-order assemblies or clusters in response to cell activation via the IgE receptor. Clus-DoC 10 analysis identified a subset of these clusters with a high degree of interaction between 5-LO and 11 FLAP that specifically correlates with the time course of LTC 4 synthesis, strongly suggesting 12 their role in the initiation of leukotriene biosynthesis. 13One way cells integrate signals is by the organization and disassembly of higher order 26 multiprotein assemblies; especially those regulated by transient weak interactions [13, 14]. 27These structures must be assembled at the right time with the correct spatial localization. 28Modulating their composition and organization by orchestrating changes in the relationships 29 between member proteins, such as by post-translational modification, can determine cellular 30 responses to stimuli [13][14][15]. 31 Leukotrienes (LTs), arachidonate 5-lipoxygenase (5-LO; UniProtKB: P09917) products 32 of arachidonic acid (AA) metabolism, play a major role in initiating and amplifying inflammatory 33 diseases, ranging from asthma to cardiovascular disease. Because of the dire consequences of 34 the unregulated activation of this pathway, cells have evolved a series of complex control 35 mechanisms to prevent the inadvertent initiation of LT synthesis. One strategy is based on the 36 spatial segregation of the biosynthetic enzymes in different cellular compartments. In resting 37 cells, 5-LO is localized in the nucleus and cytosol, and cytosolic phospholipase A 2 (cPLA 2 ; 38 UniProtKB: P47712) is in the cytosol [16][17][18][19][20][21]. In activated mast cells, calcium influx triggers 39 translocation of cPLA 2 to the Golgi and ER membranes [16, 17], and of 5-LO to the nuclear 40 envelope [19, 21], a main site LT synthesis. cPLA 2 releases AA from the membrane 41 phospholipids. To form the core of the LT synthetic complex on the nuclear envelope, [22, 23], 42 AA associates with the homotrimeric integral membrane scaffold protein, arachidonate 5-43 lipoxygenase-activating protein (FLAP; UniProtKB: P20292). This event alters the relationship 44 between the N-and C-terminal domains of FLAP [23] leading to recruitment of membrane-45 associated 5-LO [22, 23]. Though this is a transient, weak interaction requiring chemical 46 crosslinking to identify biochem...