Researchers describe how cells take out the trash to prevent disease

November 11, 2008

Garbage collectors are important for removing trash; without them waste accumulates and can quickly become a health hazard. Similarly, individual cells that make up such biological organisms as humans also have sophisticated methods for managing waste.

For example, cells have developed complex systems for recycling, reusing and disposing of damaged, nonfunctional waste proteins. When such systems malfunction and these proteins accumulate, they can become toxic, resulting in many diseases, including Alzheimer's, cystic fibrosis and developmental disorders.

Scott Emr, director of the Weill Institute for Cell and Molecular Biology at Cornell, and colleagues, describe in detail how cells recycle protein waste in two recent papers appearing in the journals Cell and Developmental Cell.

"We are interested in understanding how cells deal with garbage," said Emr. "It's really a very sophisticated recycling system."

Cells use enzymes known as proteases to break down proteins into their component amino acids in the cytoplasm -- the fluid inside the cell's surface membrane. Those amino acids are then reused to make new proteins. But water-insoluble proteins embedded in the cell's membrane require a much more complicated recycling process.

Emr's paper in Cell identifies a family of proteins that controls the removal of unwanted water-insoluble proteins from the membrane. The research advances understanding of how cells recognize which proteins out of hundreds on a cell's surface should be removed. For example, hormone receptors at a cell's surface signal such processes within the cell as growth and proliferation. To inactivate these receptors and terminate the growth signal, receptors are tagged for removal. Failure to inactivate can lead to developmental diseases and cancer.

The researchers, including postdoctoral fellows Jason MacGurn and Chris Stefan, identified nine related proteins in yeast, which they named the "arrestin-related trafficking" adaptors or ARTs. Each of these proteins identifies and binds to a different set of membrane proteins. Once bound, the ART protein links to an enzyme that attaches a chemical tag for that protein's removal. The ARTs are found in both yeast and humans, suggesting the fundamental nature of their function.

Once the protein is tagged, the piece of membrane with the targeted protein forms a packet, called a vesicle, that enters the cell's cytoplasm. There, the vesicle enters a larger membrane body called an endosome, which in turn dumps it into another compartment called the lysosome, where special enzymes break apart big molecules to their core units: proteins to amino acids, membranes to fatty acids, carbohydrates to sugars and nucleic acids to nucleotides, and those basic materials are then reused.

The paper in Developmental Cell, co-authored by Emr with postdoctoral fellows David Teis and Suraj Saksena, describes for the first time how a set of four proteins assemble into a highly ordered complex. This complex encircles membrane proteins that must be disposed of in the lysosome. Emr's lab was the first to identify and characterize these protein complexes (known as ESCRTs). The Developmental Cell paper describes the order of events in which the ESCRT complexes encircle and deliver "waste" proteins into vesicles destined for recycling in the lysosome.

Emr's ESCRT discovery has allowed researchers to better understand how the AIDS virus is released from its host cell. HIV hijacks the cell's ESCRT machinery during virus budding. "So, if you block the function of ESCRTs, you could block HIV release," said Emr.

Cornell University Communications

Dictyostelium: Evolution, Cell Biology, and the Development of Multicellularity (Developmental and Cell Biology Series)
by Richard H. Kessin (Author)

The Dictyostelia are soil amoebae capable of extraordinary feats of survival, motility, chemotaxis, and development. Known as the "social amoebae," these organisms have been the subjects of serious study since the 1930s. Research in this area has been instrumental in shaping general views of differentiation, morphogenesis, and communication. Beginning with the history of Dictyostelids, this book considers the problems of the evolution of this multicellular organism. Characterized by its ability to transform from a single-celled organism into an elaborate assemblage of thousands of synchronously-moving cells, each stage of its development is treated in a separate chapter. The special properties of the Dictyostelid genome are rigorously analyzed, and the methods available to manipulate...

Cells to Civilizations: The Principles of Change That Shape Life
by Enrico Coen (Author)

Cells to Civilizations is the first unified account of how life transforms itself--from the production of bacteria to the emergence of complex civilizations. What are the connections between evolving microbes, an egg that develops into an infant, and a child who learns to walk and talk? Award-winning scientist Enrico Coen synthesizes the growth of living systems and creative processes, and he reveals that the four great life transformations--evolution, development, learning, and human culture--while typically understood separately, actually all revolve around shared core principles and manifest the same fundamental recipe. Coen blends provocative discussion, the latest scientific research, and colorful examples to demonstrate the links between these critical stages in the history of...

Stem Cells For Dummies
by Lawrence S.B. Goldstein (Author), Meg Schneider (Author)

The first authoritative yet accessible guide to this controversial topicStem Cell Research For Dummies offers a balanced, plain-English look at this politically charged topic, cutting away the hype and presenting the facts clearly for you, free from debate. It explains what stem cells are and what they do, the legalities of harvesting them and using them in research, the latest research findings from the U.S. and abroad, and the prospects for medical stem cell therapies in the short and long term.Explains the differences between adult stem cells and embryonic/umbilical cord stem cellsProvides both sides of the political debate and the pros and cons of each side's opinionsIncludes medical success stories using stem cell therapy and its promise for the futureComprehensive and unbiased, Stem...

Developmental Biology: From a Cell to an Organism (Genetics & Evolution)
by Russ Hodge (Author), Nadia Rosenthal (Foreword)

Cell Migration: Developmental Methods and Protocols (Methods in Molecular Biology)
by Jun-Lin Guan (Editor)

A collection of classic, novel, and state-of-the-art methods for the study of cell migration in cultured cells, different model organisms, and specialized cells in normal development and disease. Highlights include basic assays that apply to all cell migration studies in vitro, assays in various model organisms, and assays for cancer cells, endothelial cells, and neurons both in vitro and in animal models. The protocols follow the successful Methods in Molecular Biology™ series format, each offering step-by-step laboratory instructions, an introduction outlining the principle behind the technique, lists of the necessary equipment and reagents, and tips on troubleshooting and avoiding known pitfalls.

Hormones, Signals and Target Cells in Plant Development (Developmental and Cell Biology Series)
by Daphne J. Osborne (Author), Michael T. McManus (Author)

Meristematic cells in plants become the many different types of cells found in a mature plant. This is achieved by a selective response to chemical signals both from neighbouring cells and distant tissues. It is these responses that shape the plant, its time of flowering, the sex of its flowers, its length of survival or progress to senescence and death. How do plants achieve this? This 2005 treatise addresses this question using well-chosen examples to illustrate the concept of target cells. The authors discuss how each cell has the ability to discriminate between different chemical signals, determining which it will respond to and which it will ignore. The regulation of gene expression through signal perception and signal transduction is at the core of this selectivity and the Target...

International Review Of Cytology, Volume 241: A Survey of Cell Biology (International Review of Cell and Molecular Biology) (Vol 241)
by Kwang W. Jeon (Editor)

International Review of Cytology presents current advances and comprehensive reviews in cell biology - both plant and animal. Authored by some of the foremost scientists in the field, each volume provides up-to-date information and directions for future research. Articles in this volume address biosynthesis and alternate targeting of the lysosomal cysteine protesase cathepsin L; microtubule-associated proteins and their essential roles during mitosis; molecular and functional analysis of the dictyostelium centrosome; polytene chromosomes; and insect basic leucine zipper proteins and their role in cyclic AMP dependent regulation of gene expression.

Imaginal Discs: The Genetic and Cellular Logic of Pattern Formation (Developmental and Cell Biology Series)
by Lewis I. Held Jr (Author)

Many of the 14,000 genes of Drosophila are involved in the development of imaginal discs. These hollow sacs of cells make adult structures during metamorphosis, and their study is crucial to comprehending how a larva becomes a fully-functioning fly. This book examines the genetic circuitry of the well-known 'fruit fly', tackling questions of cell assemblage and pattern formation, of the hows and the whys behind the development of the fly. After an initial examination of the proximity versus pedigree imperatives, the book delves into bristle pattern formation and disc development, with entire chapters devoted to the leg, wing, and eye. Extensive appendices include a glossary of protein domains, catalogues of well-studied genes, and an outline of signaling pathways. More than 30 wiring...

Plant Developmental Biology - Biotechnological Perspectives: Volume 1 (Plant Developmental Biology: Biotechnical Perspectives)
by Eng Chong Pua (Editor), Michael R. Davey (Editor)

Understanding the mechanisms whereby plant development is regulated is crucial for crop improvement using genetic engineering. This work, comprising two volumes, reviews recent advances in plant developmental biology and explores the possibility of their practical applications from biotechnological perspectives. Volume 1 deals with the plant model and its life cycle. Topics include the formation of shoots, roots, flowers and gametes, pollen germination, fertilization, fruit development and ripening, seed development, dormancy and germination, apomixis, male sterility and self-incompatibility. This work is a key reference for plant breeders, researchers and graduate students in the fields of plant biotechnology, agronomy, horticulture, genetics and functional genomics, and cell and...

Cell Migration: Developmental Methods and Protocols (Methods in Molecular Biology)
by Claire M. Wells (Editor), Maddy Parsons (Editor)

Cell migration is a key component of many biological processes including embryonic development, immune responses, wound healing, organ regeneration, and cancer cell metastasis, thus making it an exciting and crucial field of study. The aim of Cell Migration: Developmental Methods and Protocols, Second Edition is to bring together a wide range of these techniques from the more basic migration assays, which are still the foundation of many cell migration studies, to state-of-the-art techniques and recent technical advances. Divided into three convenient parts, the volume begins with a number of basic in vitro migration assays including measurements of wound healing, cell scattering, invasion, and chemotaxis, as well as more complex measurements of transendothelial migration, the use of...