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News - 10/13/2016 - 12:07pm

Steve Liberles named an HHMI Faculty Scholar and also receives NIH Director's Pioneer Award
Steve Liberles

Congratulations to Steve Liberles!  He recently was named an HHMI Faculty Scholar as an early career scientist with great potential.  These scholar awards are funded by the Howard Hughes Medical Institute (HHMI), the Simons Foundation, and the Bill & Melinda Gates Foundation.  For more information, see here.  Additionally, Steve was awarded an NIH Pioneer Award. For more information, see here.  

News - 09/28/2016 - 12:30pm

Rapoport Lab demonstrates how ER shaping proteins cooperate to generate and maintain a tubular ER network
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How the shape of an organelle is generated is only poorly understood, but is a fundamental question in cell biology. An interesting example is the endoplasmic reticulum (ER) as it consists of morphologically distinct domains. The ER comprises the nuclear envelope and the peripheral ER that consists of tubules connected by three-way junctions into a network, as well as interdispersed sheets. During mitosis, the tubular ER network converts into sheets. Two protein families, the reticulons (Rtns) and DP1 stabilize the high membrane curvature of tubules in cross-section. Fusion is mediated by membrane-bound GTPases of the dynamin family, called atlastins (ATLs) in metazoans. A third protein, termed lunapark, is reported to be involved in ER morphology and its exact role is unknown. Work from the Rapoport Lab, published in eLife, has elucidated the interrelationship between ATL, Rtns/DP1, and Lnp, using mammalian cells and frog egg extracts. Surprisingly, ATL is not only required to form an ER network, but also to maintain it. A balance between ATL and Rtn activity is needed for network maintenance; high concentrations of Rtn disassemble the ER into vesicles, but this can be reversed by increasing the concentration of ATL. The results suggest a model in which ATL tethers and fuses tubules stabilized by Rtns. Lnp subsequently moves into three-way junctions and probably stabilizes them. Loss-of-function of Lnp in both mammalian cells and frog egg extracts leads to the expansion of peripheral sheets. During mitosis, Lnp is phosphorylated and inactivated, suggesting that Lnp may contribute to the characteristic tubule-to-sheet transition of the ER.

(A) A tubular ER network was assembled from the interphase frog egg extracts.

(B) The addition of a cytosolic fragment of Lnp into the frog egg extracts converted the tubular ER network into sheets. 

News - 09/14/2016 - 1:14pm

Puigserver Lab connects mitochondrial heterogeneity to metastasis
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Metabolic reprogramming in cancer cells is tightly associated with tumor progression but the effect of metabolic regulatory circuits on metastasis processes is poorly understood. New work from the Puigserver lab, published in Nature, reports that mitochondrial heterogeneity driven through the transcriptional coactivator PGC1a defines populations of melanoma cells with different metastatic capacity. Mechanistically, a PGC1a transcriptional axis suppresses a subset of integrin genes that are known to influence invasion and metastasis. This axis is the target of BRAF inhibitors that independently of its cytostastic effects suppress metastasis through integrin signaling. Thus, PGC1a -mediated mitochondrial heterogeneity is important during melanoma progression changing in response to different signals including nutrients, and switching between survival-proliferation and invasion-metastasis.

News - 09/08/2016 - 9:42am

John Flanagan receives the 2016 António Champalimaud Vision Award
John Flanagan

John Flanagan is one of four researchers who have won this year’s António Champalimaud Vision Award, which recognizes their groundbreaking research into the connection between the eyes and the brain and its implications for novel vision therapies. First awarded in 2007, the António Champalimaud Vision Award is supported by the World Health Organization and the International Agency for the Prevention of Blindness’ Vision 2020 - The Right to Sight global initiative. This award was covered by the Associated Press and the New York Times. Congratulations, John!

News - 08/15/2016 - 9:37am

Yuan Lab discovers the role of RIPK1 in mediating axonal degeneration in amyotrophic lateral sclerosis (ALS)
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Axonal degeneration is frequently observed before the death of neuronal cell bodies in patients with neurodegenerative disorders including ALS and contributes significantly to neurological disability. While blocking axonal degeneration may represent an important therapeutic goal, the mechanism of axonal degeneration is unclear. In a recent paper published in Science by Yuan lab, Ito et al. investigated the role of RIPK1 in Optn-/- mice. Loss-of-function mutations in the Optineurin (Optn) gene have been implicated in both familial and sporadic cases of ALS. The authors demonstrated that optineurin actively suppressed RIPK1-dependent signaling by regulating its turnover. Loss-of-Optn led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery, including RIPK1, RIPK3 and MLKL, in the CNS. Furthermore, RIPK1/RIPK3-mediated axonal pathology was commonly observed in SOD1G93A transgenic mice and pathological samples from human ALS. Thus, RIPK1/RIPK3 plays a critical role in mediating progressive axonal degeneration and inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration.

News - 07/27/2016 - 9:24am

Haigis Lab identifies a novel program of mitochondrial proteome remodeling and metabolic specialization in naïve T cell activation
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To initiate an immune response against pathogens, a small number of T cells within the polyclonal repertoire need to proliferate rapidly to generate large numbers of effector cells that can clear pathogens. To generate the precursors required for macromolecular synthesis, energy and stress response, the T cells activate anabolic metabolism that is coupled with increased mitochondrial mass. In a recent publication in Cell Metabolism, the Haigis Lab uses T cell activation to address a fundamental question in mitochondrial biology: Does biogenesis merely replicates existing mitochondria, or generates a distinct population of mitochondria with specialized functions? Noga Ron-Harel and co-workers, in collaboration with the Gygi and Sharpe labs, show that naïve T cell activation induces a unique program of synchronized mitochondrial biogenesis and proteome remodeling, giving rise to mitochondria with a distinct proteomic signature that drives one-carbon (1C) metabolism. They demonstrate for the first time that mitochondrial 1C metabolism is important for de-novo purine biosynthesis and redox control in T cells. Genetic inhibition of mitochondrial 1C metabolism impaired antigen-specific T cell proliferation and survival in vitro and in vivo. In sum, this study identifies 1C metabolism as an early and essential metabolic signature of naïve T cell activation, and shows that mitochondrial proliferation gives rise to a new population of organelles with distinct and specialized functions. 

News - 07/01/2016 - 4:28pm

Liberles Lab deconstructs gut-to-brain signals of the vagus nerve
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The vagus nerve is a key body-brain connection that monitors the respiratory, cardiovascular, and digestive systems. Within the gastrointestinal tract, vagal sensory neurons detect a diversity of stimuli including nutrients, nausea-inducing toxins, and mechanical stretch of the stomach and intestine. In a recent publication in Cell, the Liberles Lab identified two classes of vagal gut-to-brain neurons that exert powerful and opposing effects on digestion. Genetically guided anatomical mapping reveals that vagal GPR65 neurons densely innervate intestinal villi near the pyloric sphincter, vagal GLP1R neurons instead target the stomach, and both neuron types innervate dedicated brainstem subnuclei. Optogenetic stimulation of vagal GPR65 neurons selectively blocks gastric contractions without impacting breathing or heart rate, and in vivo ganglion imaging reveals that GPR65 and GLP1R neurons differentially respond to intestinal food and stomach stretch. Delineating gut-to-brain sensory neurons provides a needed foundation for understanding neural control of gastrointestinal physiology.

News - 06/29/2016 - 11:51am

Gygi lab defines the ways in which genetic variants affect global protein abundance
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Harnessing natural genetic variants is a powerful tool for introducing genetic perturbations into a model organism. At the Jackson laboratories a cohort of genetic diverse mice known as the diversity outbred mice was created for the purpose of genetic mapping. The mice harbor millions of genetic variants which creates system-wide genetic perturbations in a single population. The Gygi lab, in collaboration with the Jackson laboratories, explored this model to better understand how variants influence protein expression (Chick et al., Nature, 2016). The results from study show that local genetic regulation is mostly dictated by the central dogma. However, distant regulation was almost exclusively through post-transcriptional mechanisms. Their analysis was able to link the abundance of one protein to one or many other proteins revealing many novel protein-protein associations. This approach has a distinct advantage of interactions maps because the association isn’t always dependent on physical interaction. 

News - 05/26/2016 - 2:02pm

Spiegelman Lab identifies new signaling mechanism that regulates thermogenic activity of “healthy” fat
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Reactive oxygen species (ROS) are thought of as toxic byproducts that cause injury to our tissues and drive pathologies associated with aging.   However, recent evidence is emerging showing that under certain conditions ROS can be important signals in healthy tissue.  In this study, the Spiegelman Lab examined these ROS signals in brown adipose tissue, which contain cells that have the specialized ability to burn stored fats as heat and combat obesity and diabetes.  They found that increases in ROS levels in brown adipose supported thermogenesis in living mouse models.  Moreover, they demonstrated that ROS signals involved the direct modification by ROS of key functional targets including the critical thermogenic protein uncoupling protein 1 (UCP1).  These findings suggest that modification of ROS processes and this newfound signaling site on UCP1 provide new and unexpected ways of manipulating thermogenesis to combat obesity and diabetes. 

News - 05/10/2016 - 4:35pm

Brugge lab uncovers important role for transaminases in proliferating cells
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In order to proliferate, cells must reproduce their biomass by acquiring nutrients from their environment and using them to synthesize macromolecules. Using a 3D tissue culture model combined with quantitative metabolomics and proteomics, members of the Brugge and Gygi labs have identified a mechanism by which proliferating cells use glutamate to support the biosynthesis of other non-essential amino acids (Coloff et al, Cell Metabolism, 2016). In proliferating cells, transaminases that make use of both the carbon and nitrogen from glutamate are utilized to generate amino acids and to fuel the TCA cycle. When cells exit the cell cycle, they reduce transaminase expression and induce an alternative enzyme, glutamate dehydrogenase, which no longer makes use of glutamate-derived nitrogen, thereby reducing amino acid biosynthesis. Importantly, this pathway appears to be used by rapidly proliferating cells from a variety of tissues and organisms, as well as by most rapidly proliferating tumor cells. This work highlights the importance of achieving a detailed understanding of the mechanisms by which cells utilize nutrients if we hope to target the aberrant metabolism observed in cancer cells as cancer therapy.