Related Experiment Video

Updated: May 13, 2026

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
05:33

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines

Published on: November 9, 2020

Proteasome inhibition enhances lysosome-mediated targeted protein degradation

Ahmed M Elshazly1,2,3, Nayyerehalsadat Hosseini1, Janakiram Vangala1

  • 1Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA.

Cell Death & Disease
|May 11, 2026
PubMed

Insights

Cancer cells activate adaptive autophagy in response to proteasome inhibitors. This study developed an autophagy-targeting chimera (AUTAC) to degrade Mcl1, enhancing proteasome inhibitor efficacy and promoting cancer cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Proteasome inhibitors are used for multiple myeloma and mantle cell lymphoma, but cancer cells develop resistance.
  • Cancer cells activate nuclear factor erythroid 2-related factor 1 (NRF1) to upregulate proteasome and autophagy genes, counteracting proteasome inhibition.
  • This adaptive response reduces proteotoxic stress, diminishing proteasome inhibitor effectiveness.

Purpose of the Study:

  • To investigate leveraging the adaptive autophagy response therapeutically instead of suppressing it.
  • To design an autophagy-targeting chimera (AUTAC) for selective degradation of the anti-apoptotic protein Mcl1 via the lysosome.
  • To determine if combining proteasome inhibitors with Mcl1 AUTAC enhances cancer cell death.

Main Methods:

  • Designed an autophagy-targeting chimera (AUTAC) to induce lysosomal degradation of Mcl1.
  • Investigated the mechanism of AUTAC-mediated degradation, including ubiquitination and cargo receptor involvement.
  • Tested the combination of a proteasome inhibitor (carfilzomib) and Mcl1 AUTAC in vitro and in vivo models.

Main Results:

  • Lysosome-mediated Mcl1 degradation by AUTAC was amplified in the presence of proteasome inhibition, dependent on NRF1.
  • AUTAC-driven Mcl1 clearance required K63-linked ubiquitination by UBC13 and TRAF6, and p62/SQSTM1 recognition.
  • The combination of carfilzomib and Mcl1 AUTAC synergistically induced cell death in multiple myeloma and lung cancer cells, including resistant lines, and reduced tumor xenografts.

Conclusions:

  • This study presents a novel strategy to enhance proteasome inhibitor efficacy by exploiting the adaptive autophagy response.
  • The developed AUTAC compound effectively targets Mcl1 for lysosomal degradation, amplifying therapeutic effects when combined with proteasome inhibitors.
  • This work establishes a framework for amplifying lysosome-mediated targeted protein degradation for cancer therapeutics.

More Related Videos

Cycloheximide Chase Analysis of Protein Degradation in Saccharomyces cerevisiae09:05

Cycloheximide Chase Analysis of Protein Degradation in Saccharomyces cerevisiae

Published on: April 18, 2016

Assaying Proteasomal Degradation in a Cell-free System in Plants07:43

Assaying Proteasomal Degradation in a Cell-free System in Plants

Published on: March 26, 2014

Related Concept Videos

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...
Regulated Protein Degradation02:58

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Regulated Protein Degradation02:58

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
The Proteasome Structure01:17

The Proteasome Structure

The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...