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Journal of Cell Science Aug 2023Peroxisomes are involved in a multitude of metabolic and catabolic pathways, as well as the innate immune system. Their dysfunction is linked to severe... (Review)
Review
Peroxisomes are involved in a multitude of metabolic and catabolic pathways, as well as the innate immune system. Their dysfunction is linked to severe peroxisome-specific diseases, as well as cancer and neurodegenerative diseases. To ensure the ability of peroxisomes to fulfill their many roles in the organism, more than 100 different proteins are post-translationally imported into the peroxisomal membrane and matrix, and their functionality must be closely monitored. In this Review, we briefly discuss the import of peroxisomal membrane proteins, and we emphasize an updated view of both classical and alternative peroxisomal matrix protein import pathways. We highlight different quality control pathways that ensure the degradation of dysfunctional peroxisomal proteins. Finally, we compare peroxisomal matrix protein import with other systems that transport folded proteins across membranes, in particular the twin-arginine translocation (Tat) system and the nuclear pore.
Topics: Membrane Proteins; Peroxisomes; Protein Transport; Intracellular Membranes
PubMed: 37552037
DOI: 10.1242/jcs.260999 -
Microbiology and Molecular Biology... Dec 2023The HIV-1 capsid, composed of approximately 1,200 copies of the capsid protein, encases genomic RNA alongside viral nucleocapsid, reverse transcriptase, and integrase... (Review)
Review
The HIV-1 capsid, composed of approximately 1,200 copies of the capsid protein, encases genomic RNA alongside viral nucleocapsid, reverse transcriptase, and integrase proteins. After cell entry, the capsid interacts with a myriad of host factors to traverse the cell cytoplasm, pass through the nuclear pore complex (NPC), and then traffic to chromosomal sites for viral DNA integration. Integration may very well require the dissolution of the capsid, but where and when this uncoating event occurs remains hotly debated. Based on size constraints, a long-prevailing view was that uncoating preceded nuclear transport, but recent research has indicated that the capsid may remain largely intact during nuclear import, with perhaps some structural remodeling required for NPC traversal. Completion of reverse transcription in the nucleus may further aid capsid uncoating. One canonical type of host factor, typified by CPSF6, leverages a Phe-Gly (FG) motif to bind capsid. Recent research has shown these peptides reside amid prion-like domains (PrLDs), which are stretches of protein sequence devoid of charged residues. Intermolecular PrLD interactions along the exterior of the capsid shell impart avid host factor binding for productive HIV-1 infection. Herein we overview capsid-host interactions implicated in HIV-1 ingress and discuss important research questions moving forward. Highlighting clinical relevance, the long-acting ultrapotent inhibitor lenacapavir, which engages the same capsid binding pocket as FG host factors, was recently approved to treat people living with HIV.
Topics: Humans; Capsid; Capsid Proteins; HIV-1; Cell Nucleus; Active Transport, Cell Nucleus; HIV Infections
PubMed: 37750702
DOI: 10.1128/mmbr.00048-22 -
Brain : a Journal of Neurology Jan 2024A common pathological denominator of various neurodegenerative diseases is the accumulation of protein aggregates. Neurotoxic effects are caused by a loss of the...
A common pathological denominator of various neurodegenerative diseases is the accumulation of protein aggregates. Neurotoxic effects are caused by a loss of the physiological activity of the aggregating protein and/or a gain of toxic function of the misfolded protein conformers. In transmissible spongiform encephalopathies or prion diseases, neurodegeneration is caused by aberrantly folded isoforms of the prion protein (PrP). However, it is poorly understood how pathogenic PrP conformers interfere with neuronal viability. Employing in vitro approaches, cell culture, animal models and patients' brain samples, we show that misfolded PrP can induce aggregation and inactivation of TAR DNA-binding protein-43 (TDP-43). Purified PrP aggregates interact with TDP-43 in vitro and in cells and induce the conversion of soluble TDP-43 into non-dynamic protein assemblies. Similarly, mislocalized PrP conformers in the cytosol bind to and sequester TDP-43 in cytosolic aggregates. As a consequence, TDP-43-dependent splicing activity in the nucleus is significantly decreased, leading to altered protein expression in cells with cytosolic PrP aggregates. Finally, we present evidence for cytosolic TDP-43 aggregates in neurons of transgenic flies expressing mammalian PrP and Creutzfeldt-Jakob disease patients. Our study identified a novel mechanism of how aberrant PrP conformers impair physiological pathways by cross-seeding.
Topics: Animals; Humans; Creutzfeldt-Jakob Syndrome; DNA-Binding Proteins; Mammals; Prion Diseases; Prion Proteins; Prions
PubMed: 37669322
DOI: 10.1093/brain/awad289 -
Biochimica Et Biophysica Acta.... Feb 2024Mitochondria import 1000-1300 different precursor proteins from the cytosol. The main mitochondrial entry gate is formed by the translocase of the outer membrane (TOM... (Review)
Review
Mitochondria import 1000-1300 different precursor proteins from the cytosol. The main mitochondrial entry gate is formed by the translocase of the outer membrane (TOM complex). Molecular coupling and modification of TOM subunits control and modulate protein import in response to cellular signaling. The TOM complex functions as regulatory hub to integrate mitochondrial protein biogenesis and quality control into the cellular proteostasis network.
Topics: Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Saccharomyces cerevisiae; Mitochondria; Mitochondrial Membranes
PubMed: 37951505
DOI: 10.1016/j.bbamcr.2023.119529 -
Cell Death & Disease Nov 2023Though TDP-43 protein can be translocated into mitochondria and causes mitochondrial damage in TDP-43 proteinopathy, little is known about how TDP-43 is imported into...
Though TDP-43 protein can be translocated into mitochondria and causes mitochondrial damage in TDP-43 proteinopathy, little is known about how TDP-43 is imported into mitochondria. In addition, whether mitochondrial damage is caused by mitochondrial mislocalization of TDP-43 or a side effect of mitochondria-mediated TDP-43 degradation remains to be investigated. Here, our bioinformatical analyses reveal that mitophagy receptor gene FUNDC1 is co-expressed with TDP-43, and both TDP-43 and FUNDC1 expression is correlated with genes associated with mitochondrial protein import pathway in brain samples of patients diagnosed with TDP-43 proteinopathy. FUNDC1 promotes mitochondrial translocation of TDP-43 possibly by promoting TDP-43-TOM70 and DNAJA2-TOM70 interactions, which is independent of the LC3 interacting region of FUNDC1 in cellular experiments. In the transgenic fly model of TDP-43 proteinopathy, overexpressing FUNDC1 enhances TDP-43 induced mitochondrial damage, whereas down-regulating FUNDC1 reverses TDP-43 induced mitochondrial damage. FUNDC1 regulates mitochondria-mediated TDP-43 degradation not only by regulating mitochondrial TDP-43 import, but also by increasing LONP1 level and by activating mitophagy, which plays important roles in cytosolic TDP-43 clearance. Together, this study not only uncovers the mechanism of mitochondrial TDP-43 import, but also unravels the active role played by mitochondria in regulating TDP-43 homeostasis.
Topics: Humans; ATP-Dependent Proteases; DNA-Binding Proteins; HSP40 Heat-Shock Proteins; Membrane Proteins; Mitochondria; Mitochondrial Proteins; Mitophagy; TDP-43 Proteinopathies
PubMed: 37951930
DOI: 10.1038/s41419-023-06261-6 -
Seminars in Cell & Developmental Biology Jul 2023The biogenesis of mitochondria requires the coordinated expression of the nuclear and the mitochondrial genomes. However, the vast majority of gene products within the... (Review)
Review
The biogenesis of mitochondria requires the coordinated expression of the nuclear and the mitochondrial genomes. However, the vast majority of gene products within the organelle are encoded in the nucleus, synthesized in the cytosol, and imported into mitochondria via the protein import machinery, which permit the entry of proteins to expand the mitochondrial network. Once inside, proteins undergo a maturation and folding process brought about by enzymes comprising the unfolded protein response (UPR). Protein import and UPR activity must be synchronized and matched with mtDNA-encoded subunit synthesis for proper assembly of electron transport chain complexes to avoid proteotoxicity. This review discusses the functions of the import and UPR systems in mammalian skeletal muscle, as well as how exercise alters the equilibrium of these pathways in a time-dependent manner, leading to a new steady state of mitochondrial content resulting in enhanced oxidative capacity and improved muscle health.
Topics: Animals; Mitochondrial Proteins; Mitochondria; Muscle, Skeletal; Unfolded Protein Response; Adaptation, Physiological; Mammals
PubMed: 35063351
DOI: 10.1016/j.semcdb.2022.01.002 -
Molecular Cell Aug 2023Numerous proteins are targeted to two or multiple subcellular destinations where they exert distinct functional consequences. The balance between such differential...
Numerous proteins are targeted to two or multiple subcellular destinations where they exert distinct functional consequences. The balance between such differential targeting is thought to be determined post-translationally, relying on protein sorting mechanisms. Here, we show that mRNA location and translation rate can also determine protein targeting by modulating protein binding to specific interacting partners. Peripheral localization of the NET1 mRNA and fast translation lead to higher cytosolic retention of the NET1 protein by promoting its binding to the membrane-associated scaffold protein CASK. By contrast, perinuclear mRNA location and/or slower translation rate favor nuclear targeting by promoting binding to importins. This mRNA location-dependent mechanism is modulated by physiological stimuli and profoundly impacts NET1 function in cell motility. These results reveal that the location of protein synthesis and the rate of translation elongation act in coordination as a "partner-selection" mechanism that robustly influences protein distribution and function.
Topics: RNA, Messenger; Oncogene Proteins; Cell Nucleus; Cytosol; Protein Transport; Protein Biosynthesis; Membrane Proteins
PubMed: 37506697
DOI: 10.1016/j.molcel.2023.06.036 -
The Journal of Cell Biology Jul 2023Mitochondria critically rely on protein import and its tight regulation. Here, we found that the complex I assembly factor NDUFAF8 follows a two-step import pathway...
Mitochondria critically rely on protein import and its tight regulation. Here, we found that the complex I assembly factor NDUFAF8 follows a two-step import pathway linking IMS and matrix import systems. A weak targeting sequence drives TIM23-dependent NDUFAF8 matrix import, and en route, allows exposure to the IMS disulfide relay, which oxidizes NDUFAF8. Import is closely surveyed by proteases: YME1L prevents accumulation of excess NDUFAF8 in the IMS, while CLPP degrades reduced NDUFAF8 in the matrix. Therefore, NDUFAF8 can only fulfil its function in complex I biogenesis if both oxidation in the IMS and subsequent matrix import work efficiently. We propose that the two-step import pathway for NDUFAF8 allows integration of the activity of matrix complex I biogenesis pathways with the activity of the mitochondrial disulfide relay system in the IMS. Such coordination might not be limited to NDUFAF8 as we identified further proteins that can follow such a two-step import pathway.
Topics: Disulfides; Electron Transport Complex I; Endopeptidases; Mitochondria; Peptide Hydrolases; Biological Transport
PubMed: 37159021
DOI: 10.1083/jcb.202210019 -
Nature Communications Sep 2023The induction of type-I interferons (IFN-Is) is important for the efficacy of chemotherapy. By investigating the role of amino acids in regulation of IFN-I production...
The induction of type-I interferons (IFN-Is) is important for the efficacy of chemotherapy. By investigating the role of amino acids in regulation of IFN-I production under chemo-drug treatment in bladder cancer (BC) cells, we find an inherent AhR-dependent negative feedback to restrain STING signaling and IFN-I production. Mechanistically, in a ligand dependent manner, AhR bridges STING and CUL4B/RBX1 E3 ligase complex, facilitating STING degradation through ubiquitin-proteasome pathway. Inhibition of AhR increases STING levels and reduces tumor growth under cisplatin or STING agonist treatment. Endogenous AhR ligands are mainly consisted of tryptophan (Trp) metabolites; dietary Trp restriction, blocking the key Trp metabolism rate-limiting enzyme IDO1 or inhibition of cellular Trp importation also show similar effect as AhR inhibition. Clinically, BC patients with higher intratumoral expression of AhR or stronger intratumoral Trp metabolism (higher IDO1 or Kyn levels) that lead to higher AhR activation show worse response rate to neoadjuvant chemotherapy (NAC).
Topics: Humans; Urinary Bladder Neoplasms; Cisplatin; Urinary Bladder; Amino Acids; Interferon Type I; Cullin Proteins
PubMed: 37670034
DOI: 10.1038/s41467-023-41218-5 -
Nature Communications Jul 2023Perturbed cellular protein homeostasis (proteostasis) and mitochondrial dysfunction play an important role in neurodegenerative diseases, however, the interplay between...
Perturbed cellular protein homeostasis (proteostasis) and mitochondrial dysfunction play an important role in neurodegenerative diseases, however, the interplay between these two phenomena remains unclear. Mitochondrial dysfunction leads to a delay in mitochondrial protein import, causing accumulation of non-imported mitochondrial proteins in the cytosol and challenging proteostasis. Cells respond by increasing proteasome activity and molecular chaperones in yeast and C. elegans. Here, we demonstrate that in human cells mitochondrial dysfunction leads to the upregulation of a chaperone HSPB1 and, interestingly, an immunoproteasome-specific subunit PSMB9. Moreover, PSMB9 expression is dependent on the translation elongation factor EEF1A2. These mechanisms constitute a defense response to preserve cellular proteostasis under mitochondrial stress. Our findings define a mode of proteasomal activation through the change in proteasome composition driven by EEF1A2 and its spatial regulation, and are useful to formulate therapies to prevent neurodegenerative diseases.
Topics: Humans; Cytoplasm; Mitochondria; Peptide Elongation Factor 1; Proteasome Endopeptidase Complex; Proteostasis; Cysteine Endopeptidases
PubMed: 37433777
DOI: 10.1038/s41467-023-39642-8