An inability to rescue ribosomes that stall during protein synthesis is associated with proteotoxicity and neurodegeneration. Stalled ribosomes harbor aberrant nascent proteins attached to tRNA. In their study in NSMB, the Shao Lab identified a mechanism that coordinates tRNA and protein quality control, in which a dedicated factor specifically cleaves off the invariant 3’-CCA from peptidyl-tRNA on stalled ribosomal complexes. This releases the nascent protein for degradation and produces a novel nonfunctional tRNA species that can be recycled by a two-step process with proofreading capabilities. These findings provide insights into how cells scrutinize individual components of aberrant molecular complexes to eliminate defective products without wasting functional factors.
As reported in Cell, researchers in the Flanagan lab have made key new insights into the molecular behavior of insulin. In their publication, they describe an unexpected mechanism by which insulin triggers changes to the expression of thousands of genes throughout the genome. These findings have important health implications given that insulin dysfunction can give rise to chronic diseases such as type 1 and type 2 diabetes, and insulin resistance has been implicated in neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Moreover, excessive insulin signaling contributes to a variety of cancers. Read more about this exciting research here.
At a special ceremony on Wednesday, April 19, 2019, Dean George Q. Daley announced the creation of the Education & Fellowship Fund for Cell Biology, made possible through the generosity of Fred Goldberg, Professor of Cell Biology, and Joan Goldberg, a hematologist at Harvard Vanguard. The Goldberg endowed fund will go towards supporting talented postdoctoral fellows and graduate students, and initiatives that will strengthen and broaden educational training in the Department of Cell Biology. Thank you Fred!
Photo (l to r): Wade Harper, Ken Anderson, Joan Goldberg, Fred Goldberg, George Daley
Photo credit: Gretchen Ertl
Dr. Danesh Moazed was just named a 2019 Fellow of the American Academy of Arts and Sciences. The mission of the Academy is to champion scholarship, civil dialogue, and useful knowledge. It is one of the country’s oldest learned societies and independent policy research centers, and it convenes leaders from the academic, business, and government sectors to respond to the challenges facing the nation and the world. Other notables named to this year's class include several Harvard-affiliated researchers, as well as Barack Obama and Sonia Sotomayor! Congrats to Danesh!
Gram-negative bacteria are among the most difficult pathogen to combat, mainly due to their unique “outer membrane” which prevents most antibiotics from entering the cell. Lipopolysaccharide (LPS) is the major component of the outer membrane, and plays critical roles in antibiotic resistance. In a recent Nature paper, the Liao lab has used single-particle cryo-electron microscopy (cryo-EM) to determine a series of structures of E. coliLptB2FGC, illustrating the mechanism of LPS extraction out of the inner membrane. Together with their previous cryo-EM structures of MsbA (Wi et al, Nature 2017, doi: 10.1038/nature23649), the work from the Liao lab has provided a high-resolution view of how ABC transporters fuel the remarkable journey of LPS across two membranes and the periplasm. Their cryo-EM structures will also facilitate structure-based development of novel antibiotics.
The Chan Zuckerberg Initiative (CZI) recently announced $17 million in funding and its selection of 17 CZI Imaging Scientists — engineers, physicists, mathematicians, computer scientists, and biologists with expertise in technology development. Amazingly, 3 of the winners are current or former members of Cell Biology! Congratulations to Dr. Jennifer Waters, Director of the Nikon Imaging Center (NIC@HMS) and Lecturer in Cell Biology, who is developing the website Microlist.org. This site collates resources for research scientists using microscopy and image analysis, including courses, meetings, educational materials and job opportunities, and is one of her several education-related and data reproducibility projects that will be funded by CZI. We also congratulate Dr. Michael Weber, a former NIC postdoctoral fellow who trained under Jennifer. Michael is currently a Field Application Specialist for the Greater Boston Area and will be using CZI funding to develop microscopes and infrastructure for a virtual imaging facility, enabling light sheet microscopes to travel between research labs. Finally, bravo to Dr. Srigokul (Gokul) Upadhyayula, a postdoctoral fellow in the Kirchhausen lab who will soon be joining UC Berkeley as the scientific director for the Advanced BioImaging Center (ABC). Gokul will be building cutting-edge adaptive optical multi-functional microscopes as part of his CZI project. Read more about the CZI awards here, and see the bios and projects of Jennifer, Michael, and Gokul here.
The body’s ability to adapt to changing conditions and shifting physiologic demands is essential to survival. To do so, each cell must be able to dispose of damaged or unnecessary proteins—a quality-control mechanism critical for cellular performance and for the health of the entire organism. A recent study in PNAS from the Goldberg lab shows that intense exercise, fasting, and an array of hormones can activate cells’ built-in protein disposal system and enhance their ability to purge defective, toxic, or unneeded proteins. These findings reveal a previously unknown mechanism used by the body to rapidly turn on the molecular machinery responsible for junk-protein removal, allowing cells to adapt their protein content to meet new demands. This mechanism, the study shows, is triggered by fluctuations in hormone levels, which signal changes in physiologic conditions. Read more about this story here and here.
A longstanding dogma is that antioxidants have the ability to aid in preventing cancer development. Recently, this dogma has been called into question because many experimental studies and clinical trials have demonstrated that antioxidants can promote, rather than retard, the development of cancer. In addition, antioxidants can reduce the efficacy of cancer therapies. Therefore, it is critical to understand which cellular antioxidants are involved in these effects and how to block them to prevent cancer progression and improve cancer therapies. In a recent paper published in Cell Metabolism, Dr. Isaac Harris, a postdoctoral fellow in the Brugge lab, and his collaborators examined the role of the most abundant endogenous cellular antioxidant, glutathione, in survival of cancer cells. Although this metabolite was identified more than 130 years ago, its role in cancer cells and their response when its production is impaired are still poorly understood. A large number of cell lines from different cancer types (e.g. breast, lung, ovarian) were tested with an inhibitor of glutathione synthesis. Cancer cells were found to be remarkably resistant to any deleterious effects associated with depletion of this antioxidant. To explore how cancer cells could survive without this abundant antioxidant, Dr. Harris and colleagues utilized high-throughput genetic and pharmacologic screens to identify cellular factors that are required for resistance to glutathione depletion. These screens identified a family of proteins, termed deubiquitinases (DUBs), which play a crucial role in maintaining survival of cancer cells after inhibition of glutathione synthesis. Importantly, combined inhibition of DUBs and glutathione production led to a profound induction of death in cancer cells. These findings shed light into the roles of antioxidants in cancer cells and provide a groundwork for novel cancer therapeutics in the future.
This work was funded by the Ludwig Cancer Research, Susan G. Komen for the Cure and Canadian Institutes of Health Research (CIHR).
We congratulate Dr. Robert V. Farese Jr., Professor of Cell Biology at HMS, who was named Chair of the Department of Genetics and Complex Diseases at the Harvard T.H. Chan School of Public Health, effective January 1, 2019. He follows the leadership of Dr. Gökhan Hotamışlıgil, who served as chair of the department for 15 years.
Bob's research focuses on the structure and mechanism of lipid synthesis and storage in cellular membranes and the function of lipids in energy metabolism. He and his team discovered DGAT enzymes, which synthesize fat, and they research how this enzymatic pathway operates in physiology and diseases. Because excessive accumulation of fats and lipids underlies many metabolic diseases, his work has major implications for understanding and treating metabolic diseases, such as atherosclerosis, obesity, and diabetes. Since joining Harvard in 2014, he has operated a joint laboratory with his scientific partner, Dr. Tobias Walther, who is also a faculty member of the School of Public Health as well as a Professor of Cell Biology at HMS.
Learn more about Bob’s research here.
Dr. Davie Van Vactor was selected as the recipient of the 2019 Harold Amos Faculty Diversity Award. Congrats, Davie! This award was created to commemorate and honor the faculty of Harvard Medical School and Harvard School of Dental Medicine who have worked towards creating a more diverse and inclusive community. Thank you, Davie, for all you have done for Harvard Medical School!