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Free Radical Biology & Medicine Nov 2023Autophagy is a major clearance pathway for misfolded α-synuclein which promotes ferroptosis through NCOA4-mediated ferritin degradation. The regulation of these two...
Autophagy is a major clearance pathway for misfolded α-synuclein which promotes ferroptosis through NCOA4-mediated ferritin degradation. The regulation of these two processes to achieve improved neuroprotection in Parkinson's disease (PD) must be elucidated. Transcription factor EB (TFEB) is a master regulator of both autophagy and lysosome biogenesis, and lysosomes are important cellular iron storage organelles; however, the role of TFEB in ferroptosis and iron metabolism remains unclear. In this study, TFEB overexpression promoted the clearance of misfolded α-synuclein and prevented ferroptosis and iron overload. TFEB overexpression up-regulated transferrin receptor 1 (TfR1) synthesis and increased the localization of TfR1 in the lysosome, facilitating lysosomal iron import and transient lysosomal iron storage. TFEB overexpression increased the levels of cellular iron-safe storage proteins (both ferritin light and heavy chains). These functions in iron metabolism maintain the cellular labile iron at a low level and electrical activity, even under iron overload conditions. Notably, lower levels of cellular labile iron and the upregulation of ferritin light and heavy chains were reversed after TfR1 knockdown in cells overexpressing TFEB, indicating that TFEB regulates cellular labile iron and suppresses ferroptosis in a TfR1 dependent manner. Taken together, this evidence of the regulation of iron metabolism enriches our understanding of the function of TFEB. In addition, TFEB overexpression protects against ferroptosis and iron overload and provides a new direction and perspective for autophagy regulation in PD.
Topics: alpha-Synuclein; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Ferritins; Ferroptosis; Iron; Iron Overload; Lysosomes; Parkinson Disease; Receptors, Transferrin; Animals; Mice; Rats; PC12 Cells
PubMed: 37683766
DOI: 10.1016/j.freeradbiomed.2023.09.004 -
Cell Stress & Chaperones Jun 2024More than 99% of the mitochondrial proteome is encoded by the nucleus and requires refolding following import. Therefore, mitochondrial proteins require the coordinated... (Review)
Review
More than 99% of the mitochondrial proteome is encoded by the nucleus and requires refolding following import. Therefore, mitochondrial proteins require the coordinated action of molecular chaperones for their folding and activation. Several heat shock protein (Hsp) molecular chaperones, including members of the Hsp27, Hsp40/70, and Hsp90 families, as well as the chaperonin complex Hsp60/10 have an established role in mitochondrial protein import and folding. The "Chaperone Code" describes the regulation of chaperone activity by dynamic post-translational modifications; however, little is known about the post-translational regulation of mitochondrial chaperones. Dissecting the regulation of chaperone function is essential for understanding their differential regulation in pathogenic conditions and the potential development of efficacious therapeutic strategies. Here, we summarize the recent literature on post-translational regulation of mitochondrial chaperones, the consequences for mitochondrial function, and potential implications for disease.
Topics: Humans; Mitochondria; Molecular Chaperones; Mitochondrial Proteins; Animals; Protein Processing, Post-Translational; Heat-Shock Proteins; Protein Folding
PubMed: 38763405
DOI: 10.1016/j.cstres.2024.05.002 -
Current Opinion in Cell Biology Dec 2023The eukaryotic nucleus exhibits remarkable plasticity in size, adjusting dynamically to changes in cellular conditions such as during development and differentiation,... (Review)
Review
The eukaryotic nucleus exhibits remarkable plasticity in size, adjusting dynamically to changes in cellular conditions such as during development and differentiation, and across species. Traditionally, the supply of structural constituents to the nuclear envelope has been proposed as the principal determinant of nuclear size. However, recent experimental and theoretical analyses have provided an alternative perspective, which emphasizes the crucial role of physical forces such as osmotic pressure and chromatin repulsion forces in regulating nuclear size. These forces can be modulated by the molecular profiles that traverse the nuclear envelope and assemble in the macromolecular complex. This leads to a new paradigm wherein multiple nuclear macromolecules that are not limited to only the structural constituents of the nuclear envelope, are involved in the control of nuclear size and related functions.
Topics: Nuclear Envelope; Cell Nucleus; Chromatin; Interphase; Macromolecular Substances
PubMed: 37801797
DOI: 10.1016/j.ceb.2023.102253 -
Cell Reports Jul 2023Nutrient starvation drives yeast meiosis, whereas retinoic acid (RA) is required for mammalian meiosis through its germline target Stra8. Here, by using single-cell...
Nutrient starvation drives yeast meiosis, whereas retinoic acid (RA) is required for mammalian meiosis through its germline target Stra8. Here, by using single-cell transcriptomic analysis of wild-type and Stra8-deficient juvenile mouse germ cells, our data show that the expression of nutrient transporter genes, including Slc7a5, Slc38a2, and Slc2a1, is downregulated in germ cells during meiotic initiation, and this process requires Stra8, which binds to these genes and induces their H3K27 deacetylation. Consequently, Stra8-deficient germ cells sustain glutamine and glucose uptake in response to RA and exhibit hyperactive mTORC1/protein kinase A (PKA) activities. Importantly, expression of Slc38a2, a glutamine importer, is negatively correlated with meiotic genes in the GTEx dataset, and Slc38a2 knockdown downregulates mTORC1/PKA activities and induces meiotic gene expression. Thus, our study indicates that RA via Stra8, a chordate morphogen pathway, induces meiosis partially by generating a conserved nutrient restriction signal in mammalian germ cells by downregulating their nutrient transporter expression.
Topics: Mice; Animals; Glutamine; Adaptor Proteins, Signal Transducing; Germ Cells; Tretinoin; Meiosis; Mammals
PubMed: 37405912
DOI: 10.1016/j.celrep.2023.112749 -
Science Advances Feb 2024Lysosomal calcium (Ca) release is critical to cell signaling and is mediated by well-known lysosomal Ca channels. Yet, how lysosomes refill their Ca remains hitherto...
Lysosomal calcium (Ca) release is critical to cell signaling and is mediated by well-known lysosomal Ca channels. Yet, how lysosomes refill their Ca remains hitherto undescribed. Here, from an RNA interference screen in , we identify an evolutionarily conserved gene, , that facilitates lysosomal Ca entry in and mammalian cells. We found that its human homolog TMEM165, previously designated as a Ca/H exchanger, imports Ca pH dependently into lysosomes. Using two-ion mapping and electrophysiology, we show that TMEM165, hereafter referred to as human LCI, acts as a proton-activated, lysosomal Ca importer. Defects in lysosomal Ca channels cause several neurodegenerative diseases, and knowledge of lysosomal Ca importers may provide previously unidentified avenues to explore the physiology of Ca channels.
Topics: Animals; Humans; Calcium; Caenorhabditis elegans; Calcium Channels; Signal Transduction; Lysosomes; Calcium Signaling; Mammals; Antiporters; Cation Transport Proteins
PubMed: 38354239
DOI: 10.1126/sciadv.adk2317 -
Annual Review of Biochemistry Apr 2024Peroxisomes are organelles that play a central role in lipid metabolism and cellular redox homeostasis. The import of peroxisomal matrix proteins by peroxisomal... (Review)
Review
Peroxisomes are organelles that play a central role in lipid metabolism and cellular redox homeostasis. The import of peroxisomal matrix proteins by peroxisomal targeting signal (PTS) receptors is an ATP-dependent mechanism. However, the energy-dependent steps do not occur early during the binding of the receptor-cargo complex to the membrane but late, because they are linked to the peroxisomal export complex for the release of the unloaded receptor. The first ATP-demanding step is the cysteine-dependent monoubiquitination of the PTS receptors, which is required for recognition by the AAA+ peroxins. They execute the second ATP-dependent step by extracting the ubiqitinated PTS receptors from the membrane for release back to the cytosol. After deubiquitination, the PTS receptors regain import competence and can facilitate further rounds of cargo import. Here, we give a general overview and discuss recent data regarding the ATP-dependent steps in peroxisome protein import.
PubMed: 38621235
DOI: 10.1146/annurev-biochem-030222-111227 -
The Chinese Journal of Dental Research Mar 2024Coordination and information exchange among the various organelles ensure the precise and orderly functioning of eukaryotic cells. Interaction between the cytoplasm and... (Review)
Review
Coordination and information exchange among the various organelles ensure the precise and orderly functioning of eukaryotic cells. Interaction between the cytoplasm and nucleoplasm is crucial for many physiological processes. Macromolecular protein transport into the nucleus requires assistance from the nuclear transport system. These proteins typically contain a nuclear localisation sequence that guides them to enter the nucleus. Understanding the mechanism of nuclear import of macromolecular proteins is important for comprehending cellular processes. Investigation of disease-related alterations can facilitate the development of novel therapeutic strategies and provide additional evidence for clinical trials. This review provides an overview of the proteins involved in nuclear transport and the mechanisms underlying macromolecular protein transport.
Topics: Active Transport, Cell Nucleus; Protein Transport; Cell Nucleus; Cytoplasm; Eukaryotic Cells
PubMed: 38546518
DOI: 10.3290/j.cjdr.b5136729 -
Current Opinion in Virology Oct 2023Microtubule transport and nuclear import are functionally connected, and the nuclear pore complex (NPC) can interact with microtubule motors. For several... (Review)
Review
Microtubule transport and nuclear import are functionally connected, and the nuclear pore complex (NPC) can interact with microtubule motors. For several alphaherpesvirus proteins, nuclear localization signals (NLSs) and their interactions with specific importin-α proteins have been characterized. Here, we review recent insights on the roles of microtubule motors, capsid-associated NLSs, and importin-α proteins for capsid transport, capsid docking to NPCs, and genome release into the nucleoplasm, as well as the role of importins for nuclear viral transcription, replication, capsid assembly, genome packaging, and nuclear capsid egress. Moreover, importin-α proteins exert antiviral effects by promoting the nuclear import of transcription factors inducing the expression of interferons (IFN), cytokines, and IFN-stimulated genes, and the IFN-inducible MxB restricts capsid docking to NPCs.
Topics: Humans; Karyopherins; alpha Karyopherins; Nuclear Pore; Herpes Simplex; Alphaherpesvirinae; Capsid Proteins
PubMed: 37672874
DOI: 10.1016/j.coviro.2023.101361 -
Nature Communications Oct 2023Insects and pathogens release effectors into plant cells to weaken the host defense or immune response. While the imports of some bacterial and fungal effectors into...
Insects and pathogens release effectors into plant cells to weaken the host defense or immune response. While the imports of some bacterial and fungal effectors into plants have been previously characterized, the mechanisms of how caterpillar effectors enter plant cells remain a mystery. Using live cell imaging and real-time protein tracking, we show that HARP1, an effector from the oral secretions of cotton bollworm (Helicoverpa armigera), enters plant cells via protein-mediated endocytosis. The entry of HARP1 into a plant cell depends on its interaction with vesicle trafficking components including CTL1, PATL2, and TET8. The plant defense hormone jasmonate (JA) restricts HARP1 import by inhibiting endocytosis and HARP1 loading into endosomes. Combined with the previous report that HARP1 inhibits JA signaling output in host plants, it unveils that the effector and JA establish a defense and counter-defense loop reflecting the robust arms race between plants and insects.
Topics: Animals; Plants; Moths; Insecta; Cyclopentanes; Oxylipins; Plant Growth Regulators; Endocytosis; Gene Expression Regulation, Plant
PubMed: 37848424
DOI: 10.1038/s41467-023-42226-1 -
American Journal of Physiology. Cell... Oct 2023Mitochondria rely upon the coordination of protein import, protein translation, and proper functioning of oxidative phosphorylation (OXPHOS) complexes I-V to sustain the... (Review)
Review
Mitochondria rely upon the coordination of protein import, protein translation, and proper functioning of oxidative phosphorylation (OXPHOS) complexes I-V to sustain the activities of life for an organism. Each process is dependent upon the function of profoundly large protein complexes found in the mitochondria [translocase of the outer mitochondrial membrane (TOMM) complex, translocase of the inner mitochondrial membrane (TIMM) complex, OXPHOS complexes, mitoribosomes]. These massive protein complexes, in some instances more than one megadalton, are built up from numerous protein subunits of varying sizes, including many proteins that are ≤100-150 amino acids. However, these small proteins, termed microproteins, not only act as cogs in large molecular machines but also have important steps in inhibiting or promoting the intrinsic pathway of apoptosis, coordinate responses to cellular stress, and even act as hormones. This review focuses on microproteins that occupy the mitochondria and are critical for its function. Although the microprotein field is relatively new, researchers have long recognized the existence of these mitochondrial proteins as critical components of virtually all aspects of mitochondrial biology. Thus, recent studies estimating that hundreds of new microproteins of unknown function exist and are missing from current genome annotations suggests that the mitochondrial "microproteome" is a rich area for future biological investigation.
Topics: Mitochondria; Mitochondrial Membranes; Oxidative Phosphorylation; Apoptosis; Mitochondrial Precursor Protein Import Complex Proteins; Micropeptides
PubMed: 37642234
DOI: 10.1152/ajpcell.00189.2023