As already mentioned in brief, cellular waste disposal depends on the activities of lysosomes and proteasomes (Fig. 1).

• Lysosomes are membrane-bound organelles containing roughly 40 different acid hydrolases (i.e., enzymes that function best in acidic pH ≤ 5); these hydrolases include proteases, nucleases, lipases, glycosidases, phosphatases, and sulfatases. Lysosomal enzymes are initially synthesized in the ER lumen and then tagged with a mannose-6-phosphate (M6P) residue within the Golgi apparatus. Such M6P-modified proteins are subsequently delivered to lysosomes through trans- Golgi vesicles that express M6P receptors. The other macromolecules destined for catabolism in the lysosomes arrive by one of three other pathways (Fig. 1):

• Material internalized by fluid-phase pinocytosis or receptor-mediated endocytosis passes from plasma membrane to early endosome to late endosome, and ultimately into the lysosome. The early endosome is the first acidic compartment encountered, while proteolytic enzymes only begin significant digestion in the late endosome; late endosomes mature into lysosomes. During the maturation process, the organelle becomes progressively more acidic.

• Senescent organelles and large, denatured protein complexes are shuttled into lysosomes by a process called autophagy. Through poorly understood mechanisms, obsolete organelles are corralled by a double membrane derived from the endoplasmic reticulum; the membrane progressively expands to encircle a collection of structures and forms an autophagosome which then fuses with lysosomes and the contents are catabolized. In addition to facilitating the turnover of aged and defunct structures, autophagy is also used to preserve cell viability during nutrient depletion.

• Phagocytosis of microorganisms or large fragments of matrix or debris occurs primarily in professional phagocytes (macrophages or neutrophils). The material is engulfed to form a phagosome that subsequently fuses with a lysosome.

• Proteasomes play an important role in degrading cytosolic proteins (Fig. 1); these include denatured or misfolded proteins (akin to what occurs within the ER), as well as any other macromolecule whose lifespan needs to be regulated (e.g., transcription factors). Many proteins destined for destruction are identified by covalently binding to a small 76–amino acid protein called ubiquitin. Poly-ubiquitinated molecules are then unfolded and funneled into the polymeric proteasome complex, a cylinder containing multiple different protease activities, each with its active site pointed at the hollow core. Proteasomes digest proteins into small (6 to 12 amino acids) fragments that can subsequently be degraded to their constituent amino acids and recycled.

Fig1. Intracellular catabolism. A, Lysosomal degradation. In heterophagy (right side), lysosomes fuse with endosomes or phagosomes to facilitate the degradation of their internalized contents. The end-products may be released into the cytosol for nutrition or discharged into the extracellular space (exocytosis). In autophagy (left side), senescent organelles or denatured proteins are targeted for lysosome-driven degradation by encircling them with a double membrane derived from the endoplasmic reticulum and marked by LC3 proteins (microtubule-associated protein 1A/1B-light chain 3). Cell stressors such as nutrient depletion or certain intracellular infections can also activate the autophagocytic pathway. B, Proteasome degradation. Cytosolic proteins destined for turnover (e.g., transcription factors or regulatory proteins), senescent proteins, or proteins that have become denatured due to extrinsic mechanical or chemical stresses can be tagged by multiple ubiquitin molecules (through the activity of E1, E2, and E3 ubiquitin ligases). This marks the proteins for degradation by proteasomes, cytosolic multi-subunit complexes that degrade proteins to small peptide fragments. High levels of misfolded proteins within the endoplasmic reticulum (ER) trigger a protective unfolded protein response—engendering a broad reduction in protein synthesis, but specific increases in chaperone proteins that can facilitate protein refolding. If this is inadequate to cope with the levels of misfolded proteins, apoptosis is induced.

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مواضيع ذات صلة

Biosynthetic Machinery: Endoplasmic Reticulum and Golgi

Cytoskeleton and Cell-Cell Interactions

Plasma Membrane: Protection and Nutrient Acquisition

Cytoplasmic Structures in Prokaryotic Cell

Eukaryotic Cell Structure

Cell Differentiation

إنقسام الخلية النباتية Plant Cell Division

الرايبوسومات Ribosomes

Ameboid Movement

The Mitochondria Extract Energy From Nutrients

Synthesis of Cellular Structures by Endoplasmic Reticulum and Golgi Apparatus

Ingestion by the Cell—Endocytosis