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ScienceWeek
CELL BIOLOGY: ON LYSOSOMES
The following points are made by J. Stinchcombe et al (Science 2004 305:55):
1) The term "lysosome" was coined to convey the idea of a membrane-bound lytic organelle that contains hydrolases active at acid pH within cells. Lysosomes are thought to be the endpoint of the endocytic pathway to which proteins and extracellular particles are delivered for degradation by a number of proteases and lipases (1). However, several studies, such as those in Tetrahymena (2), hinted that lysosomes might also function as secretory organelles. Recent data has revealed that both the degradative and secretory functions of lysosomes can be finely controlled (3), providing important regulatory mechanisms in the immune system and a number of other cell types.
2) It now emerges that the use of lysosomes as secretory organelles may be even more widespread; endocytic compartments have been identified in repairing membranes in fibroblasts (4), facilitating entry of trypanosomes into cells (5), and secreting viruses (including human immunodeficiency virus [HIV]), and potentially in secreting morphogen gradients in Drosophila. What enables lysosomes to take on the dual role of secretory granule and degradative organelle? The molecular details of the mechanisms controlling lysosomal secretion are now beginning to emerge.
3) Secretory lysosomes are modified lysosomes that can undergo regulated secretion in response to external stimuli. Secretory lysosomes are found in many different cell types of the immune system and contain specialized secretory proteins required for the specialized function of that cell type in addition to lysosomal hydrolases required for protein degradation. Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, for example, secrete the pore-forming protein perforin required to initiate cell death by means of secretory lysosomes, whereas mast cells secrete the inflammatory mediator serotonin from modified lysosomes. Morphological studies reveal the colocalization of lysosomal hydrolases and secretory proteins in many cells of the immune system, whereas biochemical and functional studies point to an important role for pH in controlling the dual functions of these organelles. Lysosomal hydrolases function at acidic pH, whereas secretory proteins, such as perforin, function at neutral pH after secretion.
4) In summary: Lysosomes are membrane-bound organelles that are found in all mammalian cells and contain hydrolases and lipases required for protein and membrane degradation. In many cells of the immune system, lysosomes also contain secretory proteins that can be released by regulated exocytosis in response to an external stimulus, providing different cell types with a wide range of effector functions. Melanosomes also use a lysosome-related organelle to secrete melanin for pigmentation. Links between albinism and immunity in patients have uncovered a number of key proteins required for lysosomal secretion and have revealed a versatile secretory mechanism that can be fine-tuned by distinct interactions in different cell types.
References (abridged):
1. S. Kornfeld, I. Mellman, Annu. Rev. Cell Biol. 5, 483 (1989)
2. M. Muller, J. Cell Biol. 52, 478 (1972)
3. E. S. Trombetta, M. Ebersold, W. Garrett, M. Pypaert, I. Mellman, Science 299, 1400 (2003)
4. J. K. Jaiswal, N. W. Andrews, S. M. Simon, J. Cell Biol. 159, 625 (2002)
5. N. W. Andrews, J. Cell Biol. 158, 389 (2002)
Science http://www.sciencemag.org
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Related Material:
ON RAB PROTEINS AND INTRACELLULAR TRANSPORT
Notes by ScienceWeek
The term "endoplasmic reticulum" refers to a complex system of flattened sacs in all biological cells that have a nucleus (eukaryotes). The endoplasmic reticulum is the site of many important syntheses, including the production of new surface membrane and the intracellular transport of various biochemical entities.
The term "Golgi apparatus" refers to a compound membranous cytoplasmic organelle of eukaryotic cells, the system consisting of flattened ribosome-free vesicles arranged in a more or less regular stack. In general, the Golgi apparatus processes proteins produced by the ribosomes of the rough endoplasmic reticulum, such processing including modification of the oligosaccharides of glycoproteins, and the sorting and packaging of proteins for transport to a variety of cellular locations. The Golgi apparatus is also a major site of synthesis of polysaccharides.
The following points are made by Nava Segev (Science 2001 292:1313):
1) Eukaryotic cells are filled with membrane-bound compartments, such as the endoplasmic reticulum and Golgi apparatus, that form a transport network for newly synthesized proteins. In the exocytic pathway, "cargo proteins" destined for secretion are inserted into the endoplasmic reticulum and are transported through the various cisternae of the Golgi apparatus. The cargo proteins are then sorted into secretory vesicles in the trans-Golgi network, the proteins sorted into budding vesicles by cargo receptors that span the compartment membrane. Once loaded, the vesicles then fuse with the plasma membrane and release their cargo at the cell surface.
2) In the endocytic pathway, proteins in or at the surface of the plasma membrane are internalized into "early endosomes", and then are transported in "late endosomes" to enzyme-filled sacs called "lysosomes", where they are degraded. Like traffic police at key intersections, a family of small proteins called the "Rab guanosine triphosphatases" regulate the sorting and transport of cargo proteins. These molecular switches ensure the specific and efficient targeting of vesicles that move cargo between various cellular compartments. In addition, Rabs may be required for the formation and movement of transport vesicles, the remodeling of vesicle membranes, the coupling of individual transport steps, and the coordination of protein transport with other cellular processes.
Science http://www.sciencemag.org
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Related Material:
ON INTRACELLULAR-MEMBRANE TRANSPORT
Notes by ScienceWeek:
The term "eukaryotic cell" refers to a biological cell with internal membrane-bound compartments such as a nucleus. An essential feature of virtually every such cell and almost every subcellular compartment inside such cells is the ability to accumulate a variety of organic metabolites and inorganic ions at concentrations that are often strikingly different from those in the surrounding milieu.
The term "intracellular transport" refers to the movement of substances across membranes or organelles inside the cell. Intracellular transport is a eukaryotic phenomenon and includes the molecular and ionic traffic into and out of such organelles as the cell nucleus, *mitochondrion, *lysosome, *peroxisome, *Golgi body, and *endoplasmic reticulum.
The following points are made by V.M Olkkonen and E. Ikonen (New England J. Med. 2000 343:1095):
1) The compartmentalization of functions into distinct membrane-bound organelles is a central characteristic of eukaryotic biological cells. The protein and lipid composition of these organelles is unique, a factor vital for their proper function. This necessitates tightly controlled transport of biomolecules from their sites of synthesis or uptake to specific destinations, and in addition requires mechanisms that prevent promiscuous interactions between cellular membranes that would lead to deleterious mixing of organelle constituents. One of the major processes responsible for the correct localization of molecules within the cell is called "membrane (or vesicular) transport". In this process, membranous carrier structures bud off a donor compartment and subsequently fuse with a recipient compartment, thus delivering their membrane-associated and soluble luminal constituents to the target organelle.
2) Proteins to be transported within cells evidently contain structural information that guides them to their correct destinations. Proteins with aberrant structures are misdirected and eventually degraded, as manifested in several inherited diseases in humans, e.g., *cystic fibrosis and *Marfan's syndrome. During the 1990s, the cellular machinery responsible for decoding protein targeting information and mediating the transport processes became apparent, and several genetic diseases that directly affect the intracellular sorting and transport machinery were identified.
3) The major cellular routes of membrane transport are a) the biosynthetic pathway responsible for the transport of proteins from the endoplasmic reticulum, where they are synthesized, to the extracellular space (i.e., "secretion") or to other cellular membrane compartments; and b) the *endocytic pathway responsible for the uptake of molecules from the extracellular milieu to be used in cellular metabolism. Most membrane proteins and proteins involved in secretion (secretory proteins), as well as many lipids, are synthesized in the endoplasmic reticulum, whose luminal environment is especially suited to facilitate the proper folding of the synthesized proteins and the initial steps of the *glycosylation of proteins.
4) Proteins that are destined to be transported out of the endoplasmic reticulum move on to the *Golgi apparatus where further modifications of these proteins occur. Subsequently, the proteins are sorted according to their various destinations: the plasma membrane (e.g., ion channels, adhesion molecules, various membrane receptors), regulated secretory granules or vesicles (e.g., hormones, enzymes, neurotransmitters), or organelles of the endocytic pathway (e.g., lysosomal *hydrolysates). In the past few years, the use of novel techniques to follow transport intermediates in living cells has revealed that in vivo the carriers not only are spherical but also in many cases they form long tubular projections across the interior of the cell.
New Engl. J. Med. http://www.nejm.org
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Notes by ScienceWeek:
mitochondrion: Mitochondria (s. mitochondrion) are double-membrane enclosed organelles of eukaryotic cells. They are involved in several important biochemical pathways, including electron transport and oxidative metabolism. Various types of eukaryotic cells may contain from a few to several thousand mitochondria in each individual cell.
lysosome: A lysosome is a cytoplasmic membrane-bound vesicle 5 to 8 nanometers in diameter and containing a variety of glycoprotein hydrolytic enzymes used to digest foreign material or defective organelles.
peroxisome: A peroxisome is an organelle rich in enzymes that act on or generate hydrogen peroxide.
Golgi body: The Golgi apparatus (Golgi complex) is a collection of organelles (Golgi bodies) in eukaryotic cells that essentially function as a collecting and packaging center for substances that the cell manufactures for export.
endoplasmic reticulum: The term "endoplasmic reticulum" refers to a complex system of flattened sacs, and it is the site of many important syntheses, including the production of new surface membrane and the intracellular transport of various biochemical entities.
cystic fibrosis: An inherited disease of the exocrine glands, primarily affecting the gastrointestinal tract and respiratory systems. The "exocrine" glands are glands that secret material via excretory ducts (e.g., mucous secreting glands).
Marfan's syndrome: (Marfan disease) A connective tissue disorder caused by a mutation in a specific gene on chromosome 15q.
endocytic: In general, the term "endocytosis" refers to the uptake of external materials by cells by means of phagocytosis (uptake of particulate material) or pinocytosis (uptake of liquid material). In both cases, the cell surface membrane literally folds completely around the entity to be taken up, and the membrane-bound is in effect pulled into the cell.
glycosylation: In this context, the substitution of one or more glycosyl groups into a protein.
Golgi apparatus: See "Golgi body" above.
hydrolysates: In general, any product of hydrolysis.
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