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Cell Biology and Metabolism Program

Director: Juan S. Bonifacino, PhD

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The Cell Biology and Metabolism Program (CBMP) conducts research in various areas of molecular cell biology, including the mechanisms of intracellular protein traffic, organelle biogenesis, host-pathogen interactions, adaptive responses to environmental stresses, the biology of small non-coding RNAs and small proteins, and the regulation of the cell cycle during oogenesis. A salient feature of the CBMP is its outstanding capabilities in state-of-the-art fluorescence microscopy technologies, including various types of super-resolution microscopy. In addition, the CBMP maintains facilities for working with many model organisms, including bacteria, yeast, Drosophila, mice, and mammalian cells. Knowledge gained from the study of basic cellular processes is applied to the elucidation of the causes of human diseases, including disorders of protein traffic as well as neurodegeneration and microbial pathogenesis.

The Section on Intracellular Protein Trafficking, led by Juan Bonifacino, focuses on the molecular machinery involved in protein sorting to endosomes, lysosomes, lysosome-related organelles and various domains of the plasma membrane. Research over the past year elucidated the role of clathrin and the adaptor protein 1 (AP-1) complex in sorting of transmembrane receptors to the somatodendritic domain of hippocampal neurons and to the basolateral surface of polarized epithelial cells. The Section also demonstrated roles for AP-1 and AP-3 in sorting of the oculocutaneous albinism type 2 (OCA2) protein to melanosomes, and for the AP-2 complex in internalization of the beta-site amyloid precursor protein (APP)–cleaving enzyme 1 (BACE1), a key enzyme in the generation of the Alzheimer's disease amyloid-beta peptide.

The Section on Gamete Development, led by Mary Lilly,examines cell cycle regulation during oogenesis. Over the past year, the Section continued to examine the pathways that coordinate meiotic progression with gamete differentiation. From these studies, the Section defined the role of a structural nucleoporin, Seh1, in promoting meiotic progression and oocyte growth. In addition, the Section demonstrated that Seh1 interacts with a novel partner outside the context of the nuclear pore complex to orchestrate a response to cellular stress in the female germline. The Section continued to define the role of stress-response pathways in guiding oocytes through the early meiotic cycle.

Jennifer Lippincott-Schwartz's Section on Organelle Biology continued to investigate new features of cellular processes by using novel fluorescence imaging approaches combined with quantitative analysis and mathematical modeling. Among the areas of investigation were (i) mitochondrial morphology and its regulation of cell cycle progression and cell cycle exit into differentiation, (ii) multiscale diffusion in the mitotic fly syncytial blastoderm, (iii) Rab10 and myosin-Va mediation of insulin-stimulated GLUT4 storage vesicle translocation in adipocytes, (iv) primary cilia utilization of glycoprotein-dependent adhesion mechanisms to stabilize long-lasting cilia-cilia contacts, (v) computational modeling of cytokinetic abscission driven by ESCRT-III polymerization, (vi) super-resolution imaging by bleaching/blinking-assisted localization microscopy, and (vii) plasticity of the asialoglycoprotein receptor deciphered by ensemble FRET imaging and single-molecule–counting PALM imaging.

The Unit on Microbial Pathogenesis, headed by Matthias Machner, analyzes host-pathogen interactions during Legionnaires' disease, a potentially fatal pneumonia caused by the bacterium Legionella pneumophila. Of particular interest are bacterial proteins, so called effectors, that are delivered into the host cell cytosol, where they alter signaling processes in order to create conditions favorable for survival and replication of the pathogen. The Unit continued its in-depth analysis of the bacterial infection cycle by identifying novel host targets for translocated effectors and determining their importance for Legionella virulence. Major progress was made in the characterization of small GTPases that function as key regulators of vesicle traffic in eukaryotic cells—effectors that exploit intracellular cargo transport by chemically modifying Rab proteins.

The Section on Environmental Gene Regulation, headed by Gisela Storz, studies small, regulatory RNAs in E. coli. Many of these bacterial RNAs act analogously to eukaryotic miRNA and siRNAs to regulate mRNA stability and translation. Along with identifying additional small RNAs and characterizing their functions, the Section helped develop general tools for the study of the RNA regulators. The Section also initiated a project to identify and characterize another category of largely overlooked genes that encode small proteins of less than 50 amino acids. Systematic screens for growth conditions that lead to increased expression and for phenotypes associated with null mutations, combined with the identification of copurifying proteins, are yielding insights into the physiological roles of these small proteins.

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