How do Cells Dispose Garbage

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Cells are the smallest structural and functional units in all the life forms. Since a cell performs all the functions for its own living and for the living of the organism, carrying these functions also results in waste generation. In the same time, extracellular factors can also cause generation of waste in the cell. If this waste is not removed quickly, the cell would slowly turn into a junkyard, ultimately causing its own death and harming the neighbouring cells. Proteins are one of the four biomolecules (carbohydrates, lipids, nucleic acids and proteins) and are the main building blocks and workers to carryout various functions of the cell. Nonetheless, proteins are the primary waste material in the cell. In fact, Rudolf Schoenheimer discovered dynamic turnover of cellular proteins in 1930s, but most intracellular proteins were believed to be long-lived until the 1980s.

 When and how proteins turn into garbage?

 1. When a protein is no longer needed, as its job is over in the cell. Often proteins with regulatory jobs have such a fate, such as cyclins and transcription factors. Cyclins control progression of the cell cycle and transcription factors decide whether certain genes need to be transcribed. If such proteins stay longer than needed, the cell would not function properly and develop anomalies.

2. Irreversible damage to proteins due to intracellular stresses and environmental stresses – cysteine and methionine amino acid residues in proteins are prone to modifications by oxidative stress that occurs upon increased levels of reactive oxygen species. Heat shock can cause loss of protein conformation. Damaged proteins associate with other damaged and/or normal proteins to form protein aggregates.

3. About 1/3rd of the total proteins synthesized in the cell never get to perform the job they were made for. Such proteins are degraded immediately after their synthesis, as these proteins do not attain their functional due to misfolding and translational errors.

Is degradation of proteins the last choice?

However, degradation of a protein is the last choice in most of the cases. There are cellular machineries to repair the damage, refold the protein and correct errors. One of such machineries is the chaperone system in cells, which comprises of the heat shock proteins (HSPs). As the name speaks, HSPs are produced when cells encounter sudden rise in temperature. HSPs associate with proteins during synthesis and play crucial role in folding of proteins into functional form. HSPs also associate with misfolded proteins and try to repair the damaged ones by initiating the refolding process.  Similarly, there are specific enzymes to limit the oxidative stress (peroxidises and dismutases) and repair the oxidized proteins (reductases). However, irreparable damage turns the protein into waste.

How garbage form is differentiated from the functional form?

The next obvious challenge for a cell to identify and degrad the garbage without causing any harm to the normal form of the same protein. The answer to this challenge came from the Nobel Prize winning work of Aaron Ciechanover, Avram Hershko and Irwin Rose "for the discovery of ubiquitin-mediated protein degradation" (2004 Nobel Prize in Chemistry). The ubiquitin proteasome system (UPS) disposes off the majority of protein garbage. UPS is a multi-protein pathway with two main components: 1) the ubiquitin conjugation system, which labels the garbage protein with ubiquitin, 2) the proteasome wherein the ubiquitin labeled-protein is degraded.

Labeling the protein with ubiquitin is the step that differentiates the garbage and useful forms of the protein. Over 1000 proteins of the UPS in human cells ensure that no innocent or useful protein is sentenced to death. This specificity is further enhanced by the involvement of several other proteins that can recognize specific damages, modifications, processed products, and exposure of hydrophobic regions in proteins. The proteasome has a core particle and a regulatory particle. The RP receives the ubiquitin-labeled substrates, removes the ubiquitin for reuse, and threads-in the substrate into the core particle, which contains a proteolytic chamber wherein substrates are degraded.

What about damaged cell organelles, large molecular assemblies and protein aggregates?

However, large cellular compartments like mitochondria and chloroplast, molecular assemblies like ribosomes also need to be disposed when they get damaged or their number increases beyond the required levels. These types of waste can not be degraded by the UPC, these and protein aggregates are packed in vesicles and taken to a digestive organelle through a process known as autophagy (Greek words “auto” meaning self + “phagy” meaning eating). The digestive organelle is known as the lysosome (vacuoles in plant cells) are acidic compartments with a variety of proteases wherein the waste is degraded.

It is noteworthy that cellular garbage disposal systems follows the principle of complete recycling of the end-products, i.e. amino acids formed at the end are used for synthesis of new proteins. Failure of the cells to get rid of damaged proteins has severe consequences for the cell itself and the environment. Several neurological and age-related diseases are associated with accumulation of proteins aggregates. Similarly, defects in waste disposal pathways cause a multitude of diseases, including cancers. 

Author: Dr. Puran Singh Sijwali, Principal Scientist, CSIR-Centre for Cellular and Molecular Biology. Email: psijwali@ccmb.res.in

Posted By : ScienceIndia Administrator