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Related Concept Videos

Autophagy01:27

Autophagy

Autophagy is a self-digesting process by which a cell protects itself from threats both within and outside the cell, ranging from abnormal proteins to invading bacteria. In this process, obsolete components of the cell and invading microbes are degraded by hydrolytic enzymes active in an acidic environment of the lysosomal lumen.
An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation,...
Delivery Pathways to the Lysosome01:36

Delivery Pathways to the Lysosome

Eukaryotic cells use different mechanisms to eliminate toxic waste obsolete and worn-out substances. Lysosomes play a pivotal role in this, and hence, these substances are carried to the lysosome from other parts of the cell and extracellular space through different pathways. The most elaborately studied pathways to the lysosome are the endocytic pathways.
Endocytosis
In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
Autophagic Cell Death01:18

Autophagic Cell Death

Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and pro-apoptotic...
The Proteasome01:13

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin...
The Proteasome02:18

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
The Proteasome02:18

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...

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Related Experiment Video

Updated: Jun 23, 2026

Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy
07:20

Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy

Published on: January 31, 2025

Small bites for big problems: stepwise aggregate degradation by autophagy.

Mark S Hipp1,2, Mario Mauthe1

  • 1Department of Biomedical Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Biochemical Society Transactions
|June 22, 2026
PubMed
Summary
This summary is machine-generated.

Protein aggregates, implicated in diseases, are cleared by aggrephagy (selective autophagy). Recent findings suggest aggregates require remodeling for autophagosomal degradation, involving chaperone-mediated steps.

Keywords:
autophagycellular protein quality controlmolecular chaperonespiecemealselective autophagy receptors

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Disease Pathogenesis

Background:

  • Protein aggregates are key pathological features in neurodegenerative diseases, cardiometabolic disorders, and cancer.
  • The ubiquitin-proteasome system handles soluble misfolded proteins, while the autophagy-lysosome pathway degrades larger, persistent protein assemblies.
  • Aggrephagy, the selective autophagic clearance of protein aggregates, is crucial for cellular homeostasis.

Purpose of the Study:

  • To review current knowledge on aggrephagy, focusing on the selective clearance of protein aggregates via autophagy.
  • To discuss recent findings suggesting that protein aggregates require priming for autophagosomal degradation through chaperone-mediated remodeling.
  • To explore the mechanisms governing the recognition and degradation of protein aggregates by the autophagy machinery.

Main Methods:

  • Review of existing literature on aggrephagy and protein aggregate clearance.
  • Analysis of recent studies investigating the role of chaperone-mediated remodeling in aggrephagy.
  • Discussion of the biophysical and architectural features of aggregates that dictate their selective autophagy.

Main Results:

  • Aggrephagy substrates are determined by aggregate architecture, biophysical state, surface accessibility, and membrane capture constraints.
  • Receptor clustering is essential for initiating autophagy, but aggregate remodeling into smaller, 'aggrephagy-competent' units is often required for efficient clearance.
  • Stepwise degradation models involving p97/VCP or chaperone modules (DNAJB6-HSP70-HSP110) cooperating with the proteasome facilitate the clearance of large aggregates.

Conclusions:

  • Successful aggrephagy depends on aggregate features and upstream remodeling processes.
  • Chaperone-mediated remodeling, potentially involving p97/VCP or specific chaperone complexes, is critical for preparing aggregates for autophagosomal degradation.
  • Understanding aggrephagy mechanisms provides insights into cellular quality control and disease pathogenesis.