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Through a systematic analysis of ribophagy in mammalian cells, the Harper lab defines how ribosomes and other cytosolic proteins are eaten via autophagy in response to stress - Jan 02, 2018

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Ribosomes are abundant cellular machines regulated by assembly, supernumerary subunit turnover, and nascent chain quality control mechanisms. Moreover, nitrogen starvation in yeast has been reported to promote selective ribosome delivery to the vacuole in an autophagy conjugation system-dependent manner, a process called "ribophagy". However, whether ribophagy in mammals is selective or regulated has not been examined. Using Ribo-Keima flux reporters, Heeseon An from the Harper lab, in a recent lab report in Nature Cell Biology, found that starvation or mTOR inhibition promotes VPS34-dependent ribophagic flux, which unlike yeast, is largely ATG8 conjugation independent and occurs concomitantly with other cytosolic protein autophagic flux reporters, indicating the absence of selectivity in this process. Ribophagic flux was not induced upon inhibition of translational elongation or nascent chain uncoupling, but was induced in a comparatively selective manner upon proteotoxic stress via arsenite or chromosome mis-segregation dependent upon VPS34 and ATG8 conjugation. Unexpectedly, Heeseon found that agents typically used to induce selective autophagy also promoted increased ribosome and cytosolic protein reporter flux, suggesting significant bulk or "by-stander" autophagy during what is often considered selective autophagy. These results emphasize the importance of monitoring non-specific cargo flux when assessing selective autophagy pathways.

Congrats to recent recipients of postdoctoral fellowships! (Part 1) - Oct 24, 2017

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Congratulations are in order for numerous Cell Biology postdocs who were recently awarded prestigous fellowships!  From left to right: Dr. Vinay Eapen (Harper lab, Jane Coffin Child Memorial Fund); Dr. Ioannis Zervantonakis (Brugge lab, NIH K99/R00); Dr. Carman Man Chung Li (Brugge lab, Susan G Komen); Dr. Ben Orlando (Liao lab, American Cancer Society); and Dr. Brandon Wadas (Finley lab, NIH F32).

Wei Mi wins Outstanding Postdoc Award for Cell Biology! - Oct 24, 2017

Wei Mi

Congratulations to Dr. Wei Mi, a postdoctoral fellow in the Liao lab, who won the 2017 Outstanding Postdoc Fellow Award for the Department of Cell Biology. This award is given out annually to a postdoc in each research department by the HMS/HSDM Office of Postdoctoral Fellows. Wei's research focuses on understanding the molecular basis of lipid transport between leaflets of a cell's bilayer membrane. Specifically, he is trying to understand how certain membrane proteins, such as flippases, carry out this important cellular function. Currently, Wei is studying MsbA, a flippase found in the membranes of Gram-negative bacteria. Understanding the structure and mechanism of MsbA will be valuable in the design of antibiotics.

Haigis lab reveals metabolic recycling is a crucial source of breast cancer biomass - Oct 19, 2017

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Cancer cells increase nutrient consumption and metabolic fitness to support rapid growth and proliferation. Consequently, the tumor microenvironment (TME) accumulates metabolic by-products, such as lactate and ammonia, which are confined due to poor vascularization of the TME.  In a recent study published in Science, the Haigis lab found that the metabolic by-product ammonia accumulates in the TME of breast cancer xenograft models and has functions far beyond a metabolic waste product.  The authors used stable isotope metabolic tracing studies paired with LC-MS to detect that ammonia liberated in metabolic reactions is recycled and re-incorporated into amino acids.  This recycling enables a cancer cell to maximize the biosynthetic potential of their nitrogen.  Furthermore, the authors found that ammonia was not toxic to breast cancer cells and accelerated their rate of growth and proliferation in vitro and in vivo.  This study re-orients the notion that ammonia is a toxic metabolic by-product, and highlights a novel, biosynthetic function for ammonia in cancer. 

You can read more about this research at Science Daily, Genetic Engineering & Biotechnology News, and HMS News

New study by Brugge lab uncovers apoptotic vulnerabilities in ovarian cancer - Sep 22, 2017

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High-grade serous ovarian cancers (HGS-OvCa) frequently develop chemotherapy resistance; therefore, identification of novel therapies for the treatment of chemotherapy-resistant tumors remains an unmet need. In a recent study published in Nature Communications, the Brugge lab carried out a systematic proteomic profiling analysis of responses to PI3K/mTOR inhibition in 14 HGS-OvCa patient-derived xenografts (PDX) to identify vulnerabilities of chemotherapy-resistant ovarian cancer.  Findings from these studies showed that PI3K/mTOR inhibition strongly promotes apoptotic priming which sensitizes cells to inhibition of BCL2 family anti-apoptotic proteins. Combined inhibition of the PI3K/AKT/mTOR axis and BCL-2/BCL-Xinduces effective tumor cell death in vitro and in orthotopic mouse xenografts in vivo. By performing an in-depth analysis of the BCL-2 family of apoptotic regulators using selective inhibitors and computational modeling, the Brugge lab identified BIM, BCL-XL and MCL-1 as critical players and biomarkers in ovarian cancer cell survival. This study presents a novel systematic approach to comprehensively investigate apoptotic priming mechanisms and identify cell death vulnerabilities in HGS-OvCa.

Bob Farese announced as a 2018 Laureate Award winner by the Endocrine Society - Sep 14, 2017

Bob Farese

Bob Farese has been selected as one of 14 leaders in the endocrinology field to receive a prestigious 2018 Laureate Award from the Endocrine Society. Established in 1944, these awards recognize the highest achievements in the field of endocrinology, including groundbreaking resesarch and innovations in clinical care. Bob was awarded the Roy O. Greep Award for Outstanding Research for his seminal contributions to the understanding of cellular lipid metabolism. His work has shown how alterations in lipid synthesis and storage contribute to the pathogenesis of human diseases, in particular type 2 diabetes, and has suggested new targets for therapy. Bob also pioneered the cell biology of lipid droplets, the cellular organelle responsible for storing triglycerides and metabolic energy, including identifying hundreds of genes that govern lipid storage in cells. To learn more, please click here.

Liao lab uncovers the structural basis for LPS transport by ABC transporter MsbA - Sep 08, 2017

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Lipopolysaccharide (LPS, also known as endotoxin) in Gram-negative bacteria is critical for the bacterial survival and their resistance to antibiotics. As a critical step of LPS biosynthesis, newly produced LPS in the cytoplasmic leaflet of the inner membrane is flipped to the periplasmic leaflet by MsbA, an ATP-binding cassette transporter. In a recent study published in Nature on September 6, the Liao lab use single particle cryo-EM to obtain high-resolution snapshots of MsbA at different functional states. This study uncovers the structural basis for LPS transport, and paves the way for structural characterization of many other lipid flippases.