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News - 03/02/2017 - 12:01pm

Rapoport Lab identifies the minimal system needed to generate and maintain the tubular ER network
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How organelle shape is generated and maintained is a fundamental question in cell biology. The endoplasmic reticulum (ER) is particularly intriguing, as it consists of morphologically distinct domains, including the nuclear envelope and the peripheral ER. A major feature of the peripheral ER is a polygonal network of tubules. Previous work has identified proteins involved in ER network formation, the reticulon and REEP/Yop1 families that stabilize the high membrane curvature of tubules in cross-section, and membrane-bound GTPases that fuse ER membranes (the atlastins in metazoans and Sey1p/RHD3 in yeast and plants). In a recent paper in Nature, the Rapoport Lab has determined the minimal components needed to generate the tubular ER network. Reconstitution of S. cerevisiae Sey1p and Yop1p into liposomes yielded a tubular network upon addition of GTP. Maintenance of this network required continuous GTP hydrolysis, as the tubules quickly fragmented upon inhibition of Sey1p. The Yop1p protein could be substituted by a variety of other curvature-stabilizing proteins including those from the reticulon protein family. Interestingly, atlastin could generate a GTP-dependent network all by itself, serving both as a fusogen and curvature-stabilizing protein. These results lead to a model in which the tubular ER network can be generated with a surprisingly small set of membrane proteins that mediate membrane fusion and stabilize curvature. The network corresponds to a steady state balance of continuous membrane fusion and fragmentation.

News - 01/26/2017 - 8:51am

Shao et al. show how new tail-anchored membrane proteins are given protected time for biosynthesis before being degraded
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Protein biosynthesis and quality control must be precisely balanced to give new proteins an opportunity to mature before degrading failed intermediates that can cause disease. New work from Shao et al., published in Science, shows how a complex of three chaperones (TRC40, BAG6, and SGTA) triages a class of membrane proteins between biosynthesis and degradation. To do this, they biochemically rebuilt the triage reaction in a test tube with purified proteins and measured the kinetics of substrate flux through the complex. SGTA is the fastest at capturing new substrates to keep them uncommitted from any fate. Priority to biosynthesis is achieved by a ‘private’ and very fast substrate transfer reaction from SGTA to TRC40, which delivers substrates to the endoplasmic reticulum (ER). This transfer is analogous to a baton transfer between two runners in a relay race. Otherwise, BAG6 picks up substrates released from SGTA that have failed transfer to TRC40 and routes them for degradation. This is analogous to a relay race monitor removing a baton dropped because one of the runners was unavailable or out of place. Thus, how long SGTA can hold onto substrates (~20 sec) limits how long they have to mature. Because TRC40 and BAG6 hold onto substrates 15-30 times longer than SGTA, transfer to these chaperones effectively commits substrates to ER targeting or quality control, respectively. This work introduces molecular concepts that are generally applicable to numerous protein triage processes that are crucial for preventing the accumulation of faulty protein by-products linked to various neurodegenerative and aging diseases.

News - 01/18/2017 - 10:33am

Joan Brugge awarded 2016 American Cancer Society Medal of Honor
Joan Brugge

Joan Brugge was awarded the American Cancer Society Medal of Honor for Basic Research for her influential contributions to the identification of the protein encoded by the Src oncogene, as well as elucidating the fundamental aspects of events involved in the initiation and progression of cancer. The Medal of Honor is awarded to those who have made the most valuable contributions and impact in saving more lives from cancer through basic research, clinical research, and cancer control. For more information, please see the press release here. Congratulations, Joan!

News - 12/11/2016 - 9:23pm

Team from the Nikon Imaging Center at HMS provides a comprehensive review of super-resolution microscopy
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In a recent article in the Journal of Cell Biology, Jennifer Waters & Talley Lambert from the Nikon Imaging Center (NIC@HMS) review the current practical limitations and compromises that must be made when designing a super-resolution microscopy experiment. They also provide information and resources to help biologists navigate through common pitfalls in specimen preparation and optimization of image acquisition, and discuss errors and artifacts that may compromise the reproducibility of super-resolution microscopy data.

News - 12/01/2016 - 9:45am

Shi Lab finds that the PRC2 associated protein EPOP/C17orf96 pays a dual role in gene regulation and may contribute to cancer
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Gene regulatory networks are pivotal for many biological processes. In mouse embryonic stem cells (mESCs), the transcriptional network can be divided into three functionally distinct modules: Polycomb, Core, and Myc. The Polycomb module represses developmental genes, while the Myc module is associated with proliferative functions, and its mis-regulation is linked to cancer development. New work from the Shi lab, published in Molecular Cell (see also the Preview in the same issue), showed that, in mESCs, the Polycomb repressive complex 2 (PRC2)-associated protein EPOP/C17orf96 co-localizes at chromatin with members of the Myc and Polycomb module. EPOP interacts with the transcription elongation factor Elongin BC and the H2B deubiquitinase USP7 to modulate transcriptional processes in mESCs similar to MYC. EPOP is commonly upregulated in human cancer, and its loss impairs the proliferation of several human cancer cell lines. These findings establish EPOP as a transcriptional modulator, which impacts both Polycomb and active gene transcription in mammalian cells, and a possible involvement of EPOP in human cancerogenesis.

News - 11/04/2016 - 12:49pm

New lattice light sheet now available in the CBMF:

The Cell Biology Microscopy Facility (CBMF) is proud to announce that their new lattice light sheet microscope is up and running!  This state-of-the art instrument, designed by the lab of Nobel Prize winner Eric Betzig (Janelia Research Campus), provides unprecedented spatiotemporal resolution for imaging live samples in 3-D over time, while minimizing photo-toxicity and photobleaching.  We invite you to check it out!  Thanks to Talley Lambert of the CBMF for all his work in bringing this instrument to life!

News - 10/18/2016 - 9:57am

Puigserver Lab Finds that Bromodomain Inhibition Rescues Bioenergetic Failures Caused by Mitochondrial Complex I Mutations
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Mutations in mitochondrial proteins (either nuclear or mitochondrial-encoded) cause bioenergetic failures observed in mitochondrial diseases. Rescue of these bioenergetic defects constitutes a feasible strategy to prevent cellular deterioration that leads to cell death. New work from the Puigserver lab, published in Molecular Cell (see also the Preview in the same issue), reports that bromodomain inhibition or loss of Brd4 correct bioenergetic deficiency caused by mitochondrial disease complex I mutations. Using chemical and genome-wide CRISPR editing screens in complex I trans-mitochondrial hybrids cells, they find that chemical inhibition or loss of Brd4 rescue cell death caused by growth under conditions requiring oxidative phosphorylation for survival. Mechanistically, Brd4 controls a set of mitochondrial genes that bypass complex I mutations rewiring the electron transfer chain through complex II. These studies provide a metabolic/energetic strategy to overcome cellular failure caused by defects in mitochondrial complex I. 

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.