Professor of Molecular Biology & Genetics
Frank H.T. Rhodes Class of '56 Endowed Director of the
Weill Institute for Cell and Molecular Biology
Background:
Scott D. Emr is the Frank H.T. Rhodes Class of 1956 Professor of Molecular Biology and Genetics and Director of the Weill Institute for Cell and Molecular Biology (Weill Institute). He received his Ph.D. degree in Molecular Genetics from Harvard Medical School in 1981. Prior to joining the faculty at Cornell, he has held positions at the University of California, Berkeley (Miller Research Scholar; 1981-1983), the California Institute of Technology (Assistant and Associate Professor; 1983-1991) and the University of California, San Diego School of Medicine (Full Professor and Investigator in the Howard Hughes Medical Institute; 1991-2007). Dr. Emr counts among his early honors a Searle Scholars Award and an NSF Presidential Young Investigator Award. He has been elected a member of the National Academy of Sciences (2007), the American Academy of Arts and Sciences (2004) and the American Academy of Microbiology (1998). In 2003, he was awarded the Hansen Foundation Gold Medal Prize for elucidating intracellular sorting and transport pathways. In 2007, he was awarded the Avanti Prize for his key contributions in understanding lipid signaling pathways. He also serves as a member of the Advisory Board for the Pew Scholars Program in Biomedical Sciences supported by the Pew Charitable Trusts.
Cell Signaling and Membrane Trafficking
Our lab studies the regulation of cell signaling and membrane trafficking pathways by phosphoinositide kinases, protein kinases, selective ubiquitin modifications, and vesicle-mediated transport reactions.
All eukaryotic cells maintain an elaborate system of vesicular transport pathways that convey cargo in and out of the cell via the endocytic and secretory systems. Our long-term goal has been to define the complex regulatory processes that ensure the temporal and spatial specificity of these membrane trafficking systems. We have focused our research in two major areas: (1) endocytic trafficking and receptor down-regulation and (2) phosphoinositide lipid- and ubiquitin-dependent membrane sorting pathways.
Endocytosis and Receptor Down-Regulation
The endosomal membrane trafficking system is required for many key cellular processes including down-regulation of activated cell-surface receptors, antigen presentation, and the sorting of biosynthetic cargoes to the lysosome. A subset of late endosomes contain internal vesicles and are referred to as multivesicular bodies (MVBs). MVB vesicles form by a membrane invagination process in which the vesicles bud into the lumen of the endosome. Our work has provided insights into the mechanism and regulation of this essential transport pathway. Entry of cargo into the MVB pathway, a highly regulated event, requires both cis- and trans-acting factors. Ubiquitination of endosomal membrane cargo proteins serves as a positive sorting signal for inclusion in the intralumenal MVB vesicle. We have identified and characterized more than a dozen transport components in the MVB-sorting pathway. Several of these proteins assemble into a set of protein-sorting complexes referred to as the ESCRT complexes I, II and III (endosomal sorting complexes required for transport), the sequential activities of which are required for the recognition and sorting of ubiquitin-modified MVB cargo proteins.
Our observations indicate that both the phosphoinositide PI3P and monoubiquitin function as critical signals for the selective recruitment and activation of the endosomal sorting machinery required for receptor down-regulation. The mechanisms of assembly and function as well as the regulation of the ESCRT machinery are still poorly understood. Recently, we identified Mvb12 as a novel component of the ESCRT-I complex. Our data suggests that Mvb12, the first known regulator of the ESCRT complexes, maintains ESCRT-I in an inactive state in the cytosol and regulates the assembly of ESCRT-I and -II on the endosome, an essential step for cargo sorting in the MVB pathway.
We have begun to address the molecular mechanisms that drive assembly and dynamics of the ESCRT-III lattice. ESCRT-III function is required for the final protein-sorting step and membrane invagination during MVB vesicle formation. Our results strongly indicate that the assembly of ESCRT-III on endosomes requires an activating conformational switch from an inactive cytoplasmic monomer.
Of particular medical relevance, the ESCRT machinery has been shown to play an essential role in HIV viral budding. Topologically, the formation of MVB vesicles at the endosome and viral budding at the plasma membrane are similar. The ESCRT machinery therefore represents a new set of candidate targets for the development of antiviral drugs.
Phosphoinositide Signaling and Membrane Trafficking
We previously discovered that phosphoinositide (PI) lipids play an essential role in the regulation of membrane trafficking in both yeast and mammalian cells. PIs regulate diverse cellular processes, including cell growth, survival, differentiation, cytoskeletal organization, and membrane trafficking. Our long-term goal has been to understand how synthesis and turnover of PIPs (PI phosphates) are temporally and spatially regulated by lipid kinases and phosphatases. In addition, we have been using genetic and biochemical techniques to identify downstream targets/effectors for the structurally distinct PIPs.
We have demonstrated that activation of the Vps34 PI 3-kinase results in production of the lipid second messenger PI3P which triggers the recruitment of FYVE domain and PX domain-containing effector proteins to endosomal membranes. These effectors regulate protein trafficking in the endosomal system. Likewise, we have shown that the essential phospholipid PI4,5P2 which is generated by the well-conserved PI4P 5-kinase Mss4 in yeast functions in the regulation of endocytosis and organization of the actin cytoskeleton. Based on these and other findings, it has become clear that PI lipids form part of a complex spatial code for defining organelle identity in eukaryotic cells. The PI lipids together with Rab GTPases and SNARE proteins function as spatial and temporal regulators of membrane trafficking. Pools of specific PI lipids (as well as certain other lipids like DAG) are enriched in compartments of the secretory and endocytic pathways. The basic compartmental "lipid code" that has been characterized thus far is composed of PI3P on membranes of the endosomal system, PI3,5P2 on the lysosome, PI4P on the Golgi complex and PI4,5P2 on the plasma membrane. Compartment-specific localization of PI kinases leads to restricted synthesis/localization of PIPs.† The organelle-restricted PIPs program the transport activity of the membrane by recruiting and activating specific effector proteins (containing domains such as PH, FYVE, PX, ENTH and GLUE domains) that directly bind the head group of the PI lipids. Our recent efforts have been directed at determining the mechanisms for the selective localization and regulation of the PI lipid kinases and phosphatases that are required to spatially restrict PI lipids to their appropriate compartment(s).