Lysosomal compartment

S, Reis e Sousa C, Germain RN, Mellman I, Steinman 48 RM The formation of immunogenic major histocompatibility complex class Il-peptide ligands in lysosomal compartments of dendritic cells is regulated by inflammatory stimuli. J Exp Med 2000 191 927-936. 49... 

E). Basally internalized conjugate (F) may also be directed to a lysosomal compartment (B) but, it may also cross the cell via a non-lysosomal proteolytic compartment (G) where the PLL moiety can be selectively cleaved. Free and intact HRP (H) can then be released into the apical medium. 

Details of the mechanisms by which endocytosed material moves from the early to the late and lysosomal compartment are still poorly understood. However, portions of the EEs tubulovesicular structures may be actively transported along microtubules towards the perinuclear region of the cell in both neurons and non-neuronal cells. These endosomes on the move may enclose invaginated membranes and also internally bud off vesicles. For that reason, these complex structures are called multivesicular bodies (MVBs) [76]. Material returning by retrograde axonal transport to the neuronal cell body includes many MVBs [67]. The eventual fate of these structures may vary. Some MVBs may fuse with LEs or they may fuse with each... 

Mahnke K. Guo M, Lee S, Sepulveda H, Swain SL, Nussenzweig M, Steinman RM The dendritic cell receptor for endocytosis, DEC-205, can recycle and enhance antigen presentation via major histocompatibility complex class Il-positive lysosomal compartments. J Cell Biol 2000 151 673-684. 

Autoradiographic studies of the kidney have shown the accumulation of AS-ODN to occur almost exclusively in the proximal tubular cells [110,119]. Oberbauer et al. reported that intravenously injected AS-ODN accumulated in proximal tubular cells, and electron microscopy revealed that AS-ODN did accumulate only in the brush border or lysosomal compartment. This implies that the AS-ODNs were not completely degraded after being taken up by the proximal tubule [110]. 

Fig. I. Endocytic pathways used by cells to internalize soluble macromolecules [25] fluid-phase pinocytosis (1), adsorptive pinocytosis (2), and receptor-mediated endocytosis (pinocytosis) (6). Each of these processes involves a formation of a sealed vesicle formed from the plasma membrane which encloses part of the extracellular medium. The internalization of a polymer-drug conjugate (P-D), and targeted polymer-drug conjugate ( => —P-D) is shown. Other abbreviations — = cell surface receptor/antigen 1 = clathrin molecule X = lysosomal enzyme. Fluid-phase pinocytosis (1) and adsorptive pinocytosis (2) are nonspecific processes which direct the macromolecule into the lysosomal compartment of the cell. Once P-D is internalized, whether by (1) or (2), the resulting endosome (3) is ultimately fused with a primary lysosome (4) forming a secondary lysosome (5). In the latter compartment P-D is in contact with several types of lysosomal enzymes. The membrane of (5) is impermeable to macromolecules. Consequently, the structure of P-D may be designed in such...

The prerequisite is the knowledge of the interactions taking place in the enzyme-substrate complex. This was known for the model enzymes. However, for cathepsin B, the most important enzyme in the lysosomal compartment from the drug release point of view, only limited information was available [26], It was known that the amino acid residues in positions P2 and P3 should be... 

The lysosomal disorder SASD is characterized by accumulation of the free acid monosaccharide sialic acid in the lysosomal compartment of the cell. Diagnosis is based on the demonstration of abnormal excretion of free, not OGS-bound sialic acid in urine, coupled with accumulation of free sialic acid in cultured fibroblasts, and on microscopic evidence of vacuoles (increased and swollen lysosomes filled with light electron-lucent material in skin biopsy and peripheral blood lymphocytes). The inheritance is autosomal recessive. There are different clinical forms of this disorder an adult form, called Salla disease (SD) or Finnish sialuria (OMIM 604369) infantile SASD (ISSD OMIM 269920) and an intermediate form, severe Salla disease [3,16]. 

GAA is synthesized as a 110 kDa precursor protein, which is core-glycosylated in the ER and acquires mannose 6-phosphate (M6P) residues in the Golgi as diagrammed in Fig. 10.1. In the lysosomal compartments, the precursor protein is processed to yield an intermediate 95 kDa form and the two mature, fully active, 76 and 70 kDa, forms of GAA (Reuser et al., 1995 Raben et al., 2002). The 110 kDa form is secreted and can be detected in the media of infected cells or serum of transduced animals and the remaining forms can be found in expressing cells. 

Growth factors are active at very low concentrations, i.e. about 1 pM. They exert their effect by binding to specific cell surface receptors with very high affinity. Related factors show lower affinity for the receptors of other members of the group. Following interaction with its receptor, the growth factor is internalised and transported via endocytotic vesicles to the lysosomal compartment where... 

If the dmg is not broken down by the lytic enzymes of the lysosomes, it may be released in its active form from the lysosomal compartment into the cytoplasm and may even escape from the phagocyte, so causing a prolonged release systemic effect. Figure 5.2 depicts this macrophage mediated release of drags . 

The transition from coated vesicle to early endosome is accompanied by acidification of the vesicular lumen that continues into the late endosomal and lysosomal compartments, reaching a final pH in the perinuclear lysosome of approximately 4.5. Such acidification associated with endosome maturation provides the means by which certain viruses gain access to the cytosol. Acid-induced conformational changes in the viral proteins trigger translocation across the endosomal membrane via a fusion process. By taking advantage of the endosomal acidification, pH-sensitive liposomes, adenovirus and endosomolytic peptides have been used to facilitate the release of plasmids into the cytoplasm prior to lysosomal degradation. 

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