Chronic inflammation is linked to diverse diseases. While the immune cell component of inflammation has been well-studied, cell-intrinsic mechanisms that determine the response of target cells to inflammation are incompletely understood. In recent studies published in Nature Metabolism, the Danial lab identified a connection between mitochondrial pyruvate handling and arginine metabolism through the urea cycle as a cell-intrinsic anti-inflammatory mechanism. They found that pyruvate entry into the TCA cycle via pyruvate carboxylase (PC) leads to increased aspartate synthesis, which supports the aspartate-argininosuccinate shunt to fuel ureagenesis from arginine. This in turndiminishes arginine use for generation of nitric oxide (NO), a chief mediator of inflammatory cytotoxicity. The studies also showed that PC-directed ureagenesis can be regulated by glucose and tested the relevance of this metabolic mechanism in pancreatic beta-cells undergoing inflammation stress in diabetes. The ureagenic effect of PC sheds new insights into metabolic biology of this enzyme and may have implications for diseases where alterations in PC are observed, including diabetes, cancer and inborn errors of metabolism.
Resistance to chemotherapy is a complication frequently encountered during treatment of difficult recurring cancers. The ability of cancerous cells to resist the cytotoxic effects of chemotherapeutics is often mediated by ABC transporters such as P-glycoprotein, ABCG2, and MRP1, which function to actively pump anti-cancer drugs out of cells. Among these transporters the structure of ABCG2 is unique, with inverted topology and a lack of domain swapping between transmembrane helices. The mechanisms by which ABCG2 recognizes and transports diverse chemotherapy compounds has remained elusive.
In a recent paper published in Nature Communication, the Liao Lab determined a series of cryo-EM structures of ABCG2 bound to different chemotherapy compounds. These structures along with accompanying biochemical assays reveal how anti-cancer drugs induce a conformational switch of the transporter, and how different compounds elicit distinct effects on transporter conformation and function. These results have important implications for future drug development.
Most drugs are small molecules that cause a therapeutic effect by binding to a target protein. Some small molecules inhibit a protein’s function, whereas others work by activating the protein. In work published in Nature Chemical Biology, the King Lab reports the surprising identification of a small molecule that can do either, depending on cellular regulatory context.
The King lab has pioneered the development of small molecule inhibitors of the Anaphase-Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that is required for anaphase and mitotic exit. In work led by graduate student Katie Richeson, the paper reports the surprising finding that the APC/C inhibitor apcin can paradoxically stimulate APC/C activity under conditions when the APC/C is antagonized the spindle checkpoint, a signaling pathway that normally restrains APC/C activity during mitosis. These findings indicate that apcin causes net inhibition of APC/C when spindle checkpoint activity is low, or net activation of APC/C when spindle checkpoint activity is high, indicating that apcin can act as either an inhibitor or an activator of APC/C depending on physiological context.
Dr. Dan Finley was just elected to the Academy of Arts and Sciences, class of 2020! 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. Some fellow class members include Anne Hochschild (Chair of Microbiology at HMS), author Ann Patchett, musician Joan Baez, and filmmaker Richard Linklater. Congrats to Dan!
ER-associated protein degradation (ERAD) disposes of misfolded endoplasmic reticulum (ER) proteins. ERAD also mediates the regulated degradation of folded ER proteins and is hijacked by certain viruses. Misfolded luminal ER proteins undergo ERAD-L: they are retrotranslocated into the cytosol, polyubiquitinated, and degraded by the proteasome. ERAD-L is mediated by the Hrd1 complex, a complex of five proteins, but the mechanism of retrotranslocation has remained mysterious. In new findings published in Science, the Rapoport Lab, with the help of the lab of Maofu Liao, used cryo-electron microscopy to determine the architecture of the entire active Hrd1 complex. These structures, along with crosslinking and molecular dynamics simulation results, suggest how the Hrd1 complex recruits and retrotranslocates its substrates. The study shows that the Hrd1 complex retrotranslocates misfolded luminal ER proteins through two “half-channels” juxtaposed in a thinned membrane. This arrangement lowers the energy barrier for a polypeptide loop to pass through the membrane. The demonstrated novel mechanism may also be found in other translocation systems.
After a combined 61 years of service, Hemsley and Lunadel Matthews are retiring from our department. This power couple has worked tirelessley over the last 30 years to ensure that albs are fully stocked to function on a daily basis. They have worked in our department longer than most of us can remember, and they will be sorely missed. We thank them for their service and wish them the best on their next chapter! Learn about their future plans here.
Assistant Professor Dr. Sichen (Susan) Shao was announced as one of 22 early-career scientists and engineers in the 2019 class of Packard Fellows for Science and Engineering from the David and Lucile Packard Foundation. This $875,000 award will help the Shao Lab study the molecular mechanisms that detect and handle problems at different steps of protein biosynthesis by biochemically rebuilding cellular pathways for mechanistic and structural dissection. Recipients of this prestigious award have gone on to receive numerous accolades, including Nobel Prizes, MacArthur Fellowships, and election to the Nation Academies.