UNIT 11 – Intracellular Protein Turnover (Q&A) | MZO-001 MSCZOO | IGNOU

SAQ 1

Fill in the blanks:

a) The proteins for turnover are marked by ................... .
Answer: Ubiquitin

b) The ..................... is a sophisticated and highly specialised enzyme that degrades ubiquitinate proteins.
Answer: Proteasome

c) Enzymes that aid in the removal of ubiquitin from protein are ...................... .
Answer: Deubiquitinatng enzymes

d) ...................... catalyses the binding of ubiquitin to a specific substrate protein.
Answer: Ubiquitin-protein ligase (E3)

e) ..................... works as a channel gatekeeper, unfolding substrate protein and transferring them into the proteolytic chamber. 
Answer: 19S complex

SAQ 2

True or False

a) Phagocytosis is a route for the turnover of cell surface receptors.
Answer: False

b) Under stressful conditions, autophagy facilitates the random breakdown of proteins.
Answer: True

c) Proton pumps bring OH from the cytosol into lysosomes, making them acidic (pH 4.8).
Answer: False

d) Lysosomal protein absorption is always nonspecific.
Answer: False

e) Protein turnover in the lysosomes is catabolic.
Answer: True

TERMINAL QUESTIONS

1. What is intracellular protein turnover?

Intracellular protein turnover is the continuous and regulated process by which proteins inside a cell are synthesized (built or formed) and degraded (broken down). This process plays a vital role in maintaining the cell's internal balance, known as proteostasis. It ensures that old, misfolded, damaged, and excess proteins are efficiently removed and replaced with newly synthesized, functional proteins. This dynamic balance between synthesis and degradation helps the cell adapt to changes, control growth, respond to stress and perform normal physiological functions.

Each protein inside the cell has a specific half-life or lifespan. Some proteins are very short-lived and degrade within minutes, while others may last for hours or days. When a protein becomes non-functional, either due to damage or mutation, it must be removed. If this removal does not happen properly, faulty or misfolded proteins may accumulate and cause various diseases, including cancer and neurodegenerative disorders.

The turnover rate of proteins can vary depending on the cell type, the physiological state of the organism and external conditions like stress or starvation. This turnover system allows cells to efficiently recycle amino acids and maintain their internal environment.

Proper intracellular protein turnover is essential for regulation of the cell cycle, control of apoptosis (programmed cell death), antigen processing in immunity, signal transduction and removal of toxic proteins. Failure in these pathways can lead to serious cellular dysfunctions and various diseases.

There are two main types of intracellular protein turnover, depending on the pathway of degradation:

1. Ubiquitin-Proteasome Pathway (UPP):

This is the major pathway responsible for degrading short-lived, misfolded, as well as regulatory proteins in the cytoplasm and nucleus. In this process, the protein is tagged with a small molecule called ubiquitin through an ATP-dependent enzymatic reaction. Once a protein is tagged with multiple ubiquitin molecules (polyubiquitination), it is recognized and degraded by the 26S proteasome, a large multi-subunit protease complex. This pathway is especially important for controlling proteins involved in the cell cycle, transcription and signal transduction.

2. Lysosomal Pathway (Autophagy):

This pathway primarily degrades long-lived proteins, damaged organelles and large protein complexes. In macroautophagy, portions of the cytoplasm containing target proteins are enclosed in a double-membrane vesicle called the autophagosome, which then fuses with a lysosome. The acidic environment and hydrolytic enzymes inside the lysosome degrade the proteins. This pathway plays a key role during stress, starvation and development.

2. What are the key properties of the protein turnover pathways?

Protein turnover is a continuous and regulated process in which proteins inside a cell are broken down and replaced by newly synthesized ones. It is not just a recycling mechanism, but also a core regulatory process that helps maintain cellular homeostasis. Through protein turnover, cells can remove misfolded, damaged, or excess proteins and replace them with functional ones. It also allows the cell to adapt to environmental stress, control the cell cycle, regulate signaling pathways, manage growth and apoptosis. Hence, the pathways responsible for protein turnover such as the ubiquitin-proteasome system and lysosomal degradation system, both are designed with specific properties that ensure precision, efficiency and control.

The properties of protein turnover pathways can be systematically classified in two ways:
  1. Based on biochemical properties
  2. Based on physiological-level properties

1. Biochemical Properties of Protein Turnover Pathways

There are three fundamental biochemical properties that are central to protein turnover mechanisms:

1. Specificity

Protein turnover systems are highly specific. Not all proteins are degraded randomly. The system identifies target proteins based on specific degradation signals called degrons or through post-translational modifications like ubiquitination or phosphorylation. This specificity ensures that only unnecessary, misfolded, aged, or regulatory proteins are selected, protecting essential proteins from accidental destruction.

2. Energy Dependence

Protein degradation, especially via the ubiquitin-proteasome pathway, requires ATP. Energy is used at multiple steps: activation of ubiquitin by E1 enzyme, conjugation by E2, transfer by E3 ligase and unfolding of proteins before entry into the proteasome. This ATP dependence ensures that degradation is strictly regulated and does not occur spontaneously.

3. Processivity

Once a protein enters the degradation machinery, it is broken down completely into short peptides or amino acids without releasing partially degraded intermediates. This one-time, uninterrupted breakdown prevents accumulation of toxic fragments and ensures total protein clearance.

2. Physiological-Level Properties of Protein Turnover Pathways

In addition to those core biochemical traits or properties, protein turnover systems also have two important physiological-level properties:

1. Compartmentalization

Different protein turnover pathways operate in distinct cellular compartments. The ubiquitin-proteasome system mainly functions in the cytoplasm and nucleus, while the lysosomal degradation pathway functions inside lysosomes and is often used for degrading membrane proteins, extracellular proteins, or organelles (via autophagy). This spatial separation allows functional specialization and better control.

2. Coupling with Synthesis and Cellular Regulation

Protein degradation is tightly linked with protein synthesis and cellular regulatory events. When new proteins are made, old ones are often degraded to maintain balance. Moreover, regulatory proteins like cyclins, p53, or transcription factors are constantly turned over to ensure timely cellular responses. This coupling helps maintain signaling fidelity and rapid adaptability.

3. Explain the role of ubiquitin in protein turnover.

Ubiquitin is a highly conserved protein made up of 76 amino acids. It functions as a regulatory molecule in cells by tagging specific proteins for degradation. This tagging ensures that unnecessary, misfolded, damaged, or short-lived proteins are identified, and removed in a selective and controlled way. This process is essential for maintaining cellular balance and preventing harmful accumulation of proteins.

Ubiquitin does not perform the degradation itself, but by attaching to target proteins, it directs them to the proteasome, where they are broken down. This tagging function allows ubiquitin to play multiple crucial roles across different cellular processes. The major roles of ubiquitin in protein turnover can be classified as follows:

1. Protein Tagging for Degradation

The most well-established role of ubiquitin is in targeting proteins for degradation via the ubiquitin-proteasome system (UPS). In this process, multiple ubiquitin molecules are covalently attached to a target protein in the form of a polyubiquitin chain, especially through lysine-48 (K48) linkage. Once a protein is polyubiquitinated, it is recognized by the 26S proteasome, which unfolds and degrades the protein into small peptides. This process is highly energy-dependent and ATP is used at multiple steps, especially in the unfolding and translocation of the substrate protein.

2. Regulation of Cellular Processes through Controlled Degradation

Ubiquitin is also responsible for the timely removal of short-lived regulatory proteins, which include cyclins, CDK inhibitors, tumor suppressors (like p53) and certain transcription factors. The degradation of these proteins ensures proper progression of the cell cycle, stress responses and signal transduction. Since these regulatory proteins must be removed immediately after their function is complete, ubiquitin ensures precision and timing, helping the cell respond rapidly to environmental or internal changes. This function is often referred to as "regulated protein turnover" and it is critical for cellular decision-making processes.

3. Non-Degradative Regulatory Roles (Signaling Role)

Apart from tagging proteins for destruction, ubiquitin also acts as a regulatory signal in several non-degradative pathways. For example, mono-ubiquitination and non-K48 polyubiquitin chains (like K63) do not lead to degradation but instead regulate processes like DNA repair, endocytosis, protein trafficking and inflammatory signaling. In these contexts, ubiquitin does not act as a death sentence for the protein but rather as a signal to change the protein's activity, localization and interaction with other molecules.

4. What are the different routes followed by proteins targeted for lysosomal degradation?

Lysosomal degradation is one of the two major intracellular pathways responsible for maintaining protein homeostasis in eukaryotic cells, the other being the ubiquitin-proteasome system. While the proteasome primarily degrades short-lived or misfolded proteins that are tagged with ubiquitin, lysosomal degradation mainly targets long-lived cytoplasmic proteins, membrane proteins, protein aggregates, damaged organelles and extracellular proteins taken up by the cell. It plays a key role not only in general protein turnover but also in specialized physiological processes such as antigen presentation, cellular remodeling and metabolic adaptation during stress.

Proteins targeted for lysosomal degradation are transported into the lysosome through four distinct routes, each with its own mechanism of substrate selection, delivery, and regulation. These include:
  1. Macroautophagy
  2. Microautophagy
  3. Chaperone-Mediated Autophagy (CMA)
  4. Endocytosis-Mediated Degradation
Understanding these routes is essential for grasping how cells maintain internal balance and respond to environmental and metabolic signals.

[Note: Some sources also mention "phagocytosis" as an additional route for lysosomal degradation, especially for immune cells that engulf dead cells or pathogens. However, phagocytosis is primarily involved in extracellular debris and not intracellular protein turnover, so it is not usually counted among the core four routes of lysosomal degradation for proteins.]

1. Macroautophagy

Macroautophagy is the most well-studied route, often simply referred to as autophagy. In this process, a portion of the cytoplasm including protein aggregates or damaged organelles is engulfed by a double-membrane structure called the autophagosome. This vesicle then fuses with the lysosome, where the contents are degraded by lysosomal enzymes. Macroautophagy is a bulk degradation pathway that is upregulated during nutrient starvation and stress and it plays a major role in cellular quality control.

2. Microautophagy

In microautophagy, the lysosomal membrane directly invaginates or engulfs small portions of the cytoplasm, including soluble proteins. This process is non-selective and constitutive, meaning it happens at a basal level under normal conditions. It allows the lysosome to directly sample and degrade cytosolic components without the need for intermediate vesicles.

3. Chaperone-Mediated Autophagy (CMA)

CMA is a highly selective degradation pathway. Specific proteins that contain a pentapeptide motif similar to KFERQ are recognized by cytosolic chaperones like Hsc70. These proteins are then transported to the lysosomal membrane, where they bind to LAMP-2A (lysosome-associated membrane protein 2A). The substrate proteins are unfolded and directly translocated into the lysosome through this receptor. CMA is particularly important for regulating key signaling proteins and is activated under stress conditions like oxidative stress and prolonged fasting.

4. Endocytosis-Mediated Degradation

This route is used for the degradation of extracellular proteins or membrane proteins. In this process, plasma membrane proteins are internalized through endocytosis (clathrin-mediated or caveolin-mediated), forming endosomes. These early endosomes mature into late endosomes, which then fuse with lysosomes, leading to the degradation of their protein content. This pathway also includes receptor-mediated endocytosis, where specific ligand-receptor complexes are targeted for lysosomal degradation after signal transduction.









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