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The Journal of Cell Biology Jul 2024Bacteria, omnipresent in our environment and coexisting within our body, exert dual beneficial and pathogenic influences. These microorganisms engage in intricate... (Review)
Review
Bacteria, omnipresent in our environment and coexisting within our body, exert dual beneficial and pathogenic influences. These microorganisms engage in intricate interactions with the human body, impacting both human health and disease. Simultaneously, certain organelles within our cells share an evolutionary relationship with bacteria, particularly mitochondria, best known for their energy production role and their dynamic interaction with each other and other organelles. In recent years, communication between bacteria and mitochondria has emerged as a new mechanism for regulating the host's physiology and pathology. In this review, we delve into the dynamic communications between bacteria and host mitochondria, shedding light on their collaborative regulation of host immune response, metabolism, aging, and longevity. Additionally, we discuss bacterial interactions with other organelles, including chloroplasts, lysosomes, and the endoplasmic reticulum (ER).
Topics: Animals; Humans; Bacteria; Endoplasmic Reticulum; Host-Pathogen Interactions; Lysosomes; Mitochondria; Organelles
PubMed: 38748249
DOI: 10.1083/jcb.202310134 -
Nature Cell Biology Oct 2023
Topics: Humans; Cystine; Ferroptosis; Neoplasms; Lysosomes
PubMed: 37821667
DOI: 10.1038/s41556-023-01252-3 -
Cell Death and Differentiation Jan 2024Mixed lineage kinase-like protein (MLKL) forms amyloid-like polymers to promote necroptosis; however, the mechanism through which these polymers trigger cell death is...
Mixed lineage kinase-like protein (MLKL) forms amyloid-like polymers to promote necroptosis; however, the mechanism through which these polymers trigger cell death is not clear. We have determined that activated MLKL translocates to the lysosomal membrane during necroptosis induction. The subsequent polymerization of MLKL induces lysosome clustering and fusion and eventual lysosomal membrane permeabilization (LMP). This LMP leads to the rapid release of lysosomal contents into the cytosol, resulting in a massive surge in cathepsin levels, with Cathepsin B (CTSB) as a significant contributor to the ensuing cell death as it cleaves many proteins essential for cell survival. Importantly, chemical inhibition or knockdown of CTSB protects cells from necroptosis. Furthermore, induced polymerization of the MLKL N-terminal domain (NTD) also triggers LMP, leading to CTSB release and subsequent cell death. These findings clearly establish the critical role of MLKL polymerization induced lysosomal membrane permeabilization (MPI-LMP) in the process of necroptosis.
Topics: Protein Kinases; Necroptosis; Polymerization; Lysosomes; Polymers; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 37996483
DOI: 10.1038/s41418-023-01237-7 -
A noncanonical function of SKP1 regulates the switch between autophagy and unconventional secretion.Science Advances Oct 2023Intracellular degradation of proteins and organelles by the autophagy-lysosome system is essential for cellular quality control and energy homeostasis. Besides...
Intracellular degradation of proteins and organelles by the autophagy-lysosome system is essential for cellular quality control and energy homeostasis. Besides degradation, endolysosomal organelles can fuse with the plasma membrane and contribute to unconventional secretion. Here, we identify a function for mammalian SKP1 in endolysosomes that is independent of its established role as an essential component of the family of SCF/CRL1 ubiquitin ligases. We found that, under nutrient-poor conditions, SKP1 is phosphorylated on Thr, allowing its interaction with V subunits of the vacuolar ATPase (V-ATPase). This event, in turn, promotes V-ATPase assembly to acidify late endosomes and enhance endolysosomal degradation. Under nutrient-rich conditions, SUMOylation of phosphorylated SKP1 allows its binding to and dephosphorylation by the PPM1B phosphatase. Dephosphorylated SKP1 interacts with SEC22B to promote unconventional secretion of the content of less acidified hybrid endosomal/autophagic compartments. Collectively, our study implicates SKP1 phosphorylation as a switch between autophagy and unconventional secretion in a manner dependent on cellular nutrient status.
Topics: Autophagy; Cell Membrane; Endosomes; Lysosomes; Vacuolar Proton-Translocating ATPases; Humans
PubMed: 37831778
DOI: 10.1126/sciadv.adh1134 -
Chemical Society Reviews Apr 2024Targeted protein degradation (TPD) has been established as a viable alternative to attenuate the function of a specific protein of interest in both biological and... (Review)
Review
Targeted protein degradation (TPD) has been established as a viable alternative to attenuate the function of a specific protein of interest in both biological and clinical contexts. The unique TPD mode-of-action has allowed previously undruggable proteins to become feasible targets, expanding the landscape of "druggable" properties and "privileged" target proteins. As TPD continues to evolve, a range of innovative strategies, which do not depend on recruiting E3 ubiquitin ligases as in proteolysis-targeting chimeras (PROTACs), have emerged. Here, we present an overview of direct lysosome- and proteasome-engaging modalities and discuss their perspectives, advantages, and limitations. We outline the chemical composition, biochemical activity, and pharmaceutical characteristics of each degrader. These alternative TPD approaches not only complement the first generation of PROTACs for intracellular protein degradation but also offer unique strategies for targeting pathologic proteins located on the cell membrane and in the extracellular space.
Topics: Proteolysis; Proteasome Endopeptidase Complex; Lysosomes; Cell Membrane; Ubiquitin-Protein Ligases
PubMed: 38369971
DOI: 10.1039/d3cs00344b -
Current Opinion in Cell Biology Aug 2023Lipid phosphoinositides are master regulators of multiple cellular functions. Misregulation of the activity of the lipid kinases that generate phosphoinositides is... (Review)
Review
Lipid phosphoinositides are master regulators of multiple cellular functions. Misregulation of the activity of the lipid kinases that generate phosphoinositides is causative of human diseases, including cancer, neurodegeneration, developmental disorders, immunodeficiencies, and inflammatory disease. This review will present a summary of recent discoveries on the roles of two phosphoinositide kinases (PI4KA and PIKfyve), which have emerged as targets for therapeutic intervention. Phosphatidylinositol 4-kinase alpha (PI4KA) generates PI4P at the plasma membrane and PIKfyve generates PI(3,5)P at endo-lysosomal membranes. Both of these enzymes exist as multi-protein mega complexes that are under myriad levels of regulation. Human disease can be caused by either loss or gain-of-function of these complexes, so understanding how they are regulated will be essential in the design of therapeutics. We will summarize insight into how these enzymes are regulated by their protein-binding partners, with a major focus on the unanswered questions of how their activity is controlled.
Topics: Humans; Cell Membrane; Lysosomes; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Signal Transduction
PubMed: 37453227
DOI: 10.1016/j.ceb.2023.102207 -
European Journal of Medicinal Chemistry Aug 2023Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that orchestrates a diverse array of cellular processes, including vesicle transport, autophagy,... (Review)
Review
Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that orchestrates a diverse array of cellular processes, including vesicle transport, autophagy, lysosome degradation, neurotransmission, and mitochondrial activity. Hyperactivation of LRRK2 triggers vesicle transport dysfunction, neuroinflammation, accumulation of α-synuclein, mitochondrial dysfunction, and the loss of cilia, ultimately leading to Parkinson's disease (PD). Therefore, targeting LRRK2 protein is a promising therapeutic strategy for PD. The clinical translation of LRRK2 inhibitors was historically impeded by issues surrounding tissue specificity. Recent studies have identified LRRK2 inhibitors that have no effect on peripheral tissues. Currently, there are four small-molecule LRRK2 inhibitors undergoing clinical trials. This review provides a summary of the structure and biological functions of LRRK2, along with an overview of the binding modes and structure-activity relationships (SARs) of small-molecule inhibitors targeting LRRK2. It offers valuable references for developing novel drugs targeting LRRK2.
Topics: Humans; Parkinson Disease; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Autophagy; Synaptic Transmission; Lysosomes
PubMed: 37201428
DOI: 10.1016/j.ejmech.2023.115475 -
European Journal of Medicinal Chemistry Dec 2023Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of... (Review)
Review
Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of dosing, side effects and targeting "undruggable" proteins. Targeted degraders can theoretically bind any nook or cranny of targeted proteins to drive degradation. This offers convenience versus the small-molecule inhibitors that must function in a well-defined pocket. The degradation process depends mainly on two cell self-destruction mechanisms, namely the ubiquitin-proteasome system and the lysosomal degradation pathway. Various TPD strategies (e.g., proteolytic-targeting chimeras, molecular glues, lysosome-targeting chimeras, and autophagy-targeting chimeras) have been developed. These approaches hold great potential for targeting dysregulated proteins, potentially offering therapeutic benefits. In this article, we systematically review the mechanisms of various TPD strategies, potential applications to drug discovery, and recent advances. We also discuss the benefits and challenges associated with these TPD strategies, aiming to provide insight into the targeting of dysregulated proteins and facilitate their clinical applications.
Topics: Proteolysis; Proteasome Endopeptidase Complex; Autophagy; Drug Discovery; Lysosomes
PubMed: 37778240
DOI: 10.1016/j.ejmech.2023.115839 -
Science Bulletin Jun 2024Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted, but are of... (Review)
Review
Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted, but are of great clinical significance. According to statistics, over 80% of disease-related pathogenic proteins cannot be targeted by current conventional treatment methods. In recent years, with the advancement of basic research and new technologies, the development of various new technologies and mechanisms has brought new perspectives to overcome challenging drug targets. Among them, targeted protein degradation technology is a breakthrough drug development strategy for challenging drug targets. This technology can specifically identify target proteins and directly degrade pathogenic target proteins by utilizing the inherent protein degradation pathways within cells. This new form of drug development includes various types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting chimera (AUTAC), autophagy-targeting chimera (AUTOTAC), degrader-antibody conjugate (DAC). This article systematically summarizes the application of targeted protein degradation technology in the development of degraders for challenging drug targets. Finally, the article looks forward to the future development direction and application prospects of targeted protein degradation technology.
Topics: Proteolysis; Humans; Autophagy; Proteins; Lysosomes; Drug Development; Molecular Targeted Therapy; Animals
PubMed: 38614856
DOI: 10.1016/j.scib.2024.03.056 -
Journal of the American Chemical Society Aug 2023Protein dysregulation has been characterized as the cause of pathogenesis in many different diseases. For proteins lacking easily druggable pockets or catalytically...
Protein dysregulation has been characterized as the cause of pathogenesis in many different diseases. For proteins lacking easily druggable pockets or catalytically active sites, targeted protein degradation is an attractive therapeutic approach. While several methods for targeted protein degradation have been developed, there remains a demand for lower molecular weight molecules that promote efficient degradation of their targets. In this work, we describe the synthesis and validation of a series of heterobifunctional molecules that bind a protein of interest through a small molecule ligand while targeting them to the lysosome using a short gluten peptide that leverages the TG2/LRP-1 pathway. We demonstrate that this approach can be used to effectively endocytose and degrade representative secreted, cell surface, and transmembrane proteins, notably streptavidin, the vitamin B12 receptor, cubilin, and integrin αβ. Optimization of these prototypical molecules could generate pharmacologically relevant LYTAC agents.
Topics: Membrane Proteins; Biological Transport; Proteolysis; Cell Membrane; Lysosomes
PubMed: 37590164
DOI: 10.1021/jacs.3c05109