Cell Biology: Protein Breakdown and Autophagy

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Questions and Answers

What is the role of phosphatidylinositol 3-phosphate (PI3P) in the process described?

It stabilizes the mitochondrial membrane structure.

It promotes the degradation of LC3 from autophagosomes.

It initiates the recruitment of Atg5 and Atg12 for conjugation. (correct)

It directly initiates the digestion of cellular components.

Which complex is essential for the closure of the isolation membrane during autophagy?

Atg5–Atg12–Atg16L complex (correct)

Atg9–Atg2–Atg18 complex

Atg7–Atg10 complex

PINK1–Parkin complex

What is the function of Atg4 in the autophagy process?

It removes Atg9 from the phagophore.

It promotes the elongation of the isolation membrane.

It facilitates the conjugation of Atg5 and Atg12.

It degrades LC3 on the inner surface of autophagosomes. (correct)

How do PINK1 and Parkin contribute to mitophagy in Parkinson's disease?

They facilitate the selective removal of damaged mitochondria through ubiquitination. Signup and view all the answers

What condition is NOT associated with dysregulation of autophagy?

Heart disease Signup and view all the answers

Which cellular component is responsible for the degradation of proteins through the ubiquitin-dependent proteasome system?

Cytosol Signup and view all the answers

What structure surrounds constituents of the cytoplasm during autophagy?

Double membranes Signup and view all the answers

Which type of autophagy involves direct internalization of substrates through lysosomal membrane invaginations?

Microautophagy Signup and view all the answers

Which receptors are involved in targeting specific substrates to the autophagosome?

p62, NBR1, NDP52, Optineurin Signup and view all the answers

What is a primary physiological role of autophagy during periods of nutrient deprivation?

Non-selective catabolism for energy generation Signup and view all the answers

What is the role of ubiquitination in selective autophagy?

It determines which substrates are targeted to autophagosomes. Signup and view all the answers

Which organelles or substances can be eliminated through autophagy?

Proteins and microorganisms Signup and view all the answers

Which of the following statements about macrophagy is true?

It sequesters cellular components into autophagic vacuoles. Signup and view all the answers

What is released into the cytoplasm during the degradation of proteins, lipids, carbohydrates, and nucleic acids?

Amino acids, fatty acids, sugars, and nucleosides Signup and view all the answers

Which metabolic pathways are involved in catabolizing sugars to generate ATP?

Glycolysis and the pentose phosphate pathway Signup and view all the answers

What can be a substrate for gluconeogenesis in the liver?

Amino acids Signup and view all the answers

What role does ammonia play in cellular processes?

It stimulates autophagy. Signup and view all the answers

What is the process by which cytoplasmic material is engulfed into a double membrane vesicle?

Macroautophagy Signup and view all the answers

Which complex is crucial for the nucleation of autophagosomes?

Vps34 and Beclin-1/Atg6 Signup and view all the answers

What effect does the TOR pathway have on autophagy?

It inhibits autophagy. Signup and view all the answers

What initiates the activation of the ULK1 complex in autophagy?

Inhibition of mTOR Signup and view all the answers

Study Notes

Intracellular Protein Breakdown

Occurs in lysosomes and cytosol (or nucleus).
Lysosomes degrade proteins through proteases in an acidic environment.
The ubiquitin-dependent proteasome system degrades proteins in the cytosol and nucleus.
Both processes result in complete protein degradation into amino acids.

Autophagy: An Overview

A conserved cellular process across evolution.
Cytoplasmic components are enclosed by double membranes, forming vesicles.
These vesicles are delivered to lysosomes for degradation.
Autophagy eliminates misfolded proteins, proteins at the end of their lifespan, excess or damaged organelles, and even microorganisms inside cells.

Types of Autophagy

Macroautophagy: Cytoplasmic components are sequestered in a limiting membrane to form an autophagic vacuole that fuses with lysosomes.
Microautophagy: Substrates are directly internalized through invaginations of the lysosomal membrane.
Chaperone-mediated autophagy (CMA): Selective substrate proteins are translocated to lysosomes one by one after binding to a lysosomal receptor (LAMP-2A).

Autophagy under Nutrient Deprivation

Autophagy catabolizes cytoplasmic components non-selectively into autophagosomes.
Recycles and globally turns over cytoplasmic materials.
Serves as an adaptive response to generate energy sources during starvation and stress conditions.

Selective Autophagy

Specific substrates are targeted to the autophagosome by selective autophagy receptors.
Targets include protein aggregates, damaged mitochondria, and pathogens (e.g., bacteria).
Selection relies on ubiquitination of the target and binding of receptors like p62, NBR1, NDP52, and Optineurin.
These receptors contain both a ubiquitin binding domain (UBD domain) and an LC3 binding domain (LIR domain).
This process contributes to the quality control of intracellular homeostasis.

Stress and Autophagy

Multiple forms of stress activate autophagy.
The degradation of proteins, lipids, carbohydrates, and nucleic acids liberates essential building blocks:
- Amino acids
- Fatty acids
- Sugars
- Nucleosides
These building blocks are reutilized in various cellular processes:
- Sugars (glucose): Catabolized by glycolysis and the pentose phosphate pathway (PPP) to generate ATP and pyruvate for the citric acid cycle.
- Nucleosides: Used for new nucleic acid synthesis and catabolized by the PPP and glycolysis.
- Amino acids: Building blocks for new protein synthesis, ATP production, gluconeogenesis in the liver, and lipid synthesis.
- Fatty acids: Yield acetyl-CoA, which fuels the citric acid cycle, supporting ATP production and citrate generation.

Macroautophagy

The process of engulfing cytoplasmic material (organelles and protein aggregates) into a double-membrane vesicle called the autophagosome.
Autophagosome formation is initiated by the activation of the Atg1 complex (Atg1/Atg13/Atg17 and other components).
Class-III phosphatidylinositol-3-kinase (Vps34) and Beclin-1/Atg6 are essential for autophagosome nucleation, recruiting proteins and lipids.
Two ubiquitin-like systems mediate elongation and completion:
- Leads to lipidated LC3 binding to the autophagosome membrane.
The completed autophagosome fuses with the lysosome, where its contents are degraded.

Macroautophagy Regulation

Occurs at a basal level and can be induced by environmental signals:
- Nutrients
- Hormones
- Microbial pathogens
The TOR pathway is a key inhibitor of autophagy.
Autophagosome formation can be initiated through:
- TOR inhibition
- AMPK activation
These events lead to the phosphorylation of ULK1, activating it and catalyzing the phosphorylation of other components of the Atg1–ULK complex (ULK1, ULK2, Atg13, FIP200, and Atg101).
ULK1 also phosphorylates AMBRA, a component of the class-III phosphatidylinositol-3-kinase complex I (Vps34, Vps15, Atg14, and beclin-1). This enables AMBRA to relocate from the cytoskeleton to the isolation membrane.
Phosphatidylinositol 3-phosphate (PI3P), generated by Vps34 activity, binds to WIPI1 and WIPI2.
This initiates two ubiquitination-like reactions, regulating isolation membrane elongation.
- In the first reaction, Atg5 and Atg12 conjugate in the presence of Atg7 and Atg10.
- Attaching the complex containing Atg5, Atg12, and Atg16L to the isolation membrane induces the second complex to conjugate phosphatidylethanolamine to LC3.
This facilitates the closure of the isolation membrane.
Atg9 (Atg9–Atg2–Atg18 complex) cycles between endosomes, the Golgi, and the phagophore, carrying lipid components for membrane expansion.
Atg4 removes LC3-II from the outer surface of newly formed autophagosomes.
LC3 on the inner surface is degraded when the autophagosome fuses with lysosomes.

Autophagy and Medical Practice

Plays crucial roles in various pathological conditions, including:
- Infections
- Cancer
- Neurodegeneration
- Aging
Example: Parkinson's Disease
- The kinase PINK1 and the ubiquitin ligase Parkin are proteins associated with Parkinson's pathogenesis.
- PINK1 activates Parkin, which ubiquitinates VDAC1 and other mitochondrial proteins.
- This leads to the selective removal of mitochondria via autophagy (mitophagy).
- Mitophagy protects cells from damage caused by reactive oxygen species generated by dysfunctional mitochondria.
- The disruption of mitochondrial dynamics by the absence of functional PINK1 or Parkin contributes to Parkinson's disease development.
- The balance between mitochondrial biogenesis and degradation regulates mitochondrial content.

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Description

Explore the intricate processes of intracellular protein breakdown and autophagy. This quiz covers how lysosomes and the proteasome system facilitate protein degradation, along with the various types of autophagy involved in cellular maintenance. Test your knowledge on these essential cellular functions.