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Related Concept Videos

The Proteasome01:13

The Proteasome

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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...
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Regulated Protein Degradation02:58

Regulated Protein Degradation

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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...
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The Proteasome Structure01:17

The Proteasome Structure

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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...
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Export of Misfolded Proteins out of the ER01:32

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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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Lysosomal Hydrolases01:22

Lysosomal Hydrolases

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Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
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Delivery Pathways to the Lysosome01:36

Delivery Pathways to the Lysosome

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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
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Proteasome Inhibition Enhances Lysosome-mediated Targeted Protein Degradation.

Ahmed M Elshazly, Nayyerehalsadat Hosseini, Shanwei Shen

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

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    Area of Science:

    • Oncology
    • Molecular Biology
    • Cellular Stress Response

    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.
    • NRF1-mediated adaptive autophagy reduces proteotoxic stress, diminishing proteasome inhibitor effectiveness.

    Purpose of the Study:

    • To investigate therapeutic strategies that exploit, rather than suppress, the adaptive autophagy response to proteasome inhibition.
    • To design and evaluate an autophagy-targeting chimera (AUTAC) for selective degradation of the anti-apoptotic protein Mcl1.
    • To determine if combining proteasome inhibition with Mcl1 AUTAC enhances cancer cell death.

    Main Methods:

    • Development of an autophagy-targeting chimera (AUTAC) compound for lysosomal degradation of Mcl1.
    • Treatment of cancer cells with a combination of a proteasome inhibitor (carfilzomib) and Mcl1 AUTAC.
    • Assessment of NRF1-dependent mechanisms and synergistic effects on cell death in wild-type and resistant cancer cell lines.

    Main Results:

    • Lysosome-mediated Mcl1 degradation by AUTAC was significantly amplified in the presence of proteasome inhibition.
    • This amplification was dependent on the transcription factor NRF1.
    • The combination of carfilzomib and Mcl1 AUTAC synergistically induced cell death in multiple myeloma and lung cancer cells, including resistant phenotypes.

    Conclusions:

    • Combining proteasome inhibitors with Mcl1 AUTAC represents a novel strategy to enhance cancer therapy by exploiting adaptive autophagy.
    • This approach establishes a framework for amplifying lysosome-mediated targeted protein degradation for therapeutic benefit.
    • The findings have broad potential applications in cancer therapeutics and other diseases involving protein homeostasis.