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.
Dr. Maofu Liao is one of five recipients nationwide of Amgen's 2019 Young Investigator Award, which recognizes rising academic talents whose scientific contributions and commitment to academic excellence greatly impact the field of pharmaceutical research. Along with funding, Dr. Liao will have the opportunity to present a seminar at the annual Young Investigator Award Symposium in October. Congrats, Maofu!
Congratulations to Randy King, who was nominated for a 2019 Harvard Medical School Donald O’Hara Faculty Prize for Excellence in Teaching. This honor is named in memory of Donald O’Hara, PhD, a beloved teacher of Harvard medical students who served as a leader of the New Pathway Chemistry and Biology of the Cell course and as co-director of the HST course, Human Biochemistry and Metabolic Diseases. The Prize is one of the School's most important commendations for outstanding teaching accomplishments. Congrats to Randy on being nominated and recognized by HMS students as an excellent teacher!
Cation-chloride cotransporters (CCCs) mediate the electroneutral transport of chloride, potassium and/or sodium across the membrane, and play important roles in human physiology and diseases. These transporters are primary targets for some of the most commonly prescribed drugs. As described in a recent paper in Nature, the Liao Lab(in collaboration with Dr. Liang Feng’s lab at Stanford University) determines the cryo-EM structure of the Na-K-Cl cotransporter NKCC1. Structural analyses, functional characterizations and computational studies reveal the ion-translocation pathway, ion-binding sites and key residues for transport activity. These results establish a framework for understanding the physiological functions of CCCs and interpreting disease-related mutations.
Necroptosis is a necrotic programmed cell death mediated by the RIPK1-RIPK3-MLKL signaling cascade downstream of death receptors such as TNFR, Fas and TRAIL. Many neuroinflammatory diseases, including multiple slerosis, ALS, and Alzheimer's disease have been linked to activation of necroptosis. In their study published in Molecular Cell, the Yuan Lab identifies the TAM receptor tyrosine kinase family (Tyro3, Axl, Mer) as novel promoters of necroptosis. TAM kinases regulate the ultimate step in the necroptosis signaling, namely the oligomerization of MLKL, which results in the formation of a transmembrane pore and cell membrane rupture, driving the necrotic cell death. Both knockout and inhibition of TAM kinases protect mice from TNF-induced systemic inflammatory response syndrome. This study discovers a novel and unexpected role for the anti-apoptotic, oncogenic, and anti-inflammatory TAM kinases as promoters of the pro-inflammatory necroptosis, shedding light on the biological complexity of regulation of inflammation.
In order to regulate gene expression, cells utilize diverse molecular mechanisms, one of which is through mRNA modifications. In their study in Molecular Cell, the Shi Lab demonstrates that m6Am is an evolutionarily conserved mRNA modification that marks 5’ ends of mRNAs. In human cells, this mRNA modification is catalyzed only by PCIF1, a nuclear enzyme that binds CTD of RNA PolII. In this study, they further develop a genome-wide mapping methodology, m6Am-Exo-Seq, and generate a global map of this mRNA modification, which reveals a diverse set of methylated mRNAs in melanoma cells. Collaborating with Gygi and Adelman labs at HMS, they further show that m6Am does not alter mRNA transcription or stability, but it negatively impacts cap-dependent translation of methylated mRNAs in vivo and in vitro.
Proteins marked by poly-ubiquitin are degraded by the 26s proteasome. However, if proteins are too well-folded, in complexes, or located within membranes such as in the endoplasmic reticulum or mitochondria, these proteins cannot be directly degraded by the proteasome. To degrade these proteins, a protein called Cdc48 in yeast, named p97 or VCP in metazoans, must first unfold them upstream of the proteasome. Cdc48 is critical for cell viability, and mutations in p97 often lead to various neurodegenerative conditions in humans. In new findings published in Science, the Rapoport Lab used cryo-electron microscopy to understand the mechanism by which Cdc48 can interact with an unfold a wide variety of proteins. Cdc48 recruits the poly-ubiquitin signal, and initiates processing by unfolding a ubiquitin molecule, which it then uses as a handle to pull on, and unfold, attached protein substrates to prepare them for degradation by the proteasome.