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Annual Review of Plant Biology May 2023Chloroplasts are the defining plant organelles with responsibility for photosynthesis and other vital functions. To deliver these functions, they possess a complex... (Review)
Review
Chloroplasts are the defining plant organelles with responsibility for photosynthesis and other vital functions. To deliver these functions, they possess a complex proteome comprising thousands of largely nucleus-encoded proteins. Composition of the proteome is controlled by diverse processes affecting protein translocation and degradation-our focus here. Most chloroplast proteins are imported from the cytosol via multiprotein translocons in the outer and inner envelope membranes (the TOC and TIC complexes, respectively), or via one of several noncanonical pathways, and then sorted by different systems to organellar subcompartments. Chloroplast proteolysis is equally complex, involving the concerted action of internal proteases of prokaryotic origin and the nucleocytosolic ubiquitin-proteasome system (UPS). The UPS degrades unimported proteins in the cytosol and chloroplast-resident proteins via chloroplast-associated protein degradation (CHLORAD). The latter targets the TOC apparatus to regulate protein import, as well as numerous internal proteins directly, to reconfigure chloroplast functions in response to developmental and environmental signals.
Topics: Proteolysis; Proteome; Proteostasis; Chloroplasts; Ubiquitination; Chloroplast Proteins; Proteasome Endopeptidase Complex; Ubiquitin; Protein Transport; Plant Proteins
PubMed: 36854475
DOI: 10.1146/annurev-arplant-070122-032532 -
The Biochemical Journal Aug 2021Mitochondria import about 1000 proteins that are produced as precursors on cytosolic ribosomes. Defects in mitochondrial protein import result in the accumulation of... (Review)
Review
Mitochondria import about 1000 proteins that are produced as precursors on cytosolic ribosomes. Defects in mitochondrial protein import result in the accumulation of non-imported precursor proteins and proteotoxic stress. The cell is equipped with different quality control mechanisms to monitor protein transport into mitochondria. First, molecular chaperones guide unfolded proteins to mitochondria and deliver non-imported proteins to proteasomal degradation. Second, quality control factors remove translocation stalled precursor proteins from protein translocases. Third, protein translocases monitor protein sorting to mitochondrial subcompartments. Fourth, AAA proteases of the mitochondrial subcompartments remove mislocalized or unassembled proteins. Finally, impaired efficiency of protein transport is an important sensor for mitochondrial dysfunction and causes the induction of cellular stress responses, which could eventually result in the removal of the defective mitochondria by mitophagy. In this review, we summarize our current understanding of quality control mechanisms that govern mitochondrial protein transport.
Topics: Animals; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Mitophagy; Models, Biological; Protein Precursors; Protein Transport; Quality Control
PubMed: 34436539
DOI: 10.1042/BCJ20190584 -
Molecular Cell Sep 2022Peroxisomes are ubiquitous organelles whose dysfunction causes fatal human diseases. Most peroxisomal enzymes are imported from the cytosol by the receptor PEX5, which...
Peroxisomes are ubiquitous organelles whose dysfunction causes fatal human diseases. Most peroxisomal enzymes are imported from the cytosol by the receptor PEX5, which interacts with a docking complex in the peroxisomal membrane and then returns to the cytosol after monoubiquitination by a membrane-embedded ubiquitin ligase. The mechanism by which PEX5 shuttles between cytosol and peroxisomes and releases cargo inside the lumen is unclear. Here, we use Xenopus egg extract to demonstrate that PEX5 accompanies cargo completely into the lumen, utilizing WxxxF/Y motifs near its N terminus that bind a lumenal domain of the docking complex. PEX5 recycling is initiated by an amphipathic helix that binds to the lumenal side of the ubiquitin ligase. The N terminus then emerges in the cytosol for monoubiquitination. Finally, PEX5 is extracted from the lumen, resulting in the unfolding of the receptor and cargo release. Our results reveal the unique mechanism by which PEX5 ferries proteins into peroxisomes.
Topics: Carrier Proteins; Humans; Ligases; Peroxisome-Targeting Signal 1 Receptor; Peroxisomes; Protein Transport; Receptors, Cytoplasmic and Nuclear; Ubiquitin
PubMed: 35931083
DOI: 10.1016/j.molcel.2022.07.004 -
Cells Dec 2021Mitochondria play a critical role in providing energy, maintaining cellular metabolism, and regulating cell survival and death. To carry out these crucial functions,... (Review)
Review
Mitochondria play a critical role in providing energy, maintaining cellular metabolism, and regulating cell survival and death. To carry out these crucial functions, mitochondria employ more than 1500 proteins, distributed between two membranes and two aqueous compartments. An extensive network of dedicated proteins is engaged in importing and sorting these nuclear-encoded proteins into their designated mitochondrial compartments. Defects in this fundamental system are related to a variety of pathologies, particularly engaging the most energy-demanding tissues. In this review, we summarize the state-of-the-art knowledge about the mitochondrial protein import machinery and describe the known interrelation of its failure with age-related neurodegenerative and cardiovascular diseases.
Topics: Aging; Animals; Cardiovascular Diseases; Humans; Mitochondrial Membranes; Mitochondrial Proteins; Neurodegenerative Diseases; Protein Transport
PubMed: 34944035
DOI: 10.3390/cells10123528 -
Plant & Cell Physiology Jun 2018Virtually all chloroplasts in extant photosynthetic eukaryotes derive from a single endosymbiotic event that probably occurred more than a billion years ago between a... (Review)
Review
Virtually all chloroplasts in extant photosynthetic eukaryotes derive from a single endosymbiotic event that probably occurred more than a billion years ago between a host eukaryotic cell and a cyanobacterium-like ancestor. Many endosymbiont genes were subsequently transferred to the host nuclear genome, concomitant with the establishment of a system for protein transport through the chloroplast double-membrane envelope. Presently, 2,000-3,000 different nucleus-encoded chloroplast proteins must be imported into the chloroplast following their synthesis in the cytosol. The TOC (translocon at the outer envelope membrane of chloroplasts) and TIC (translocon at the inner envelope membrane of chloroplasts) complexes are protein translocation machineries at the outer and inner envelope membranes, respectively, that facilitate this chloroplast protein import with the aid of a TIC-associated ATP-driven import motor. All the essential components of this protein import system seemed to have been identified through biochemical analyses and subsequent genetic studies that initiated in the late 1990s. However, in 2013, the Nakai group reported a novel inner envelope membrane TIC complex, for which a novel ATP-driven import motor associated with this TIC complex is likely to exist. In this mini review, I will summarize these recent discoveries together with new, or reanalyzed, data presented by other groups in recent years. Whereas the precise concurrent view of chloroplast protein import is still a matter of some debate, it is anticipated that the entire TOC/TIC/ATP motor system, including any novel components, will be conclusively established in the next decade. Such findings may lead to an extensively revised view of the evolution and molecular mechanisms of chloroplast protein import.
Topics: Chloroplast Proteins; Chloroplasts; Photosynthesis; Plants; Protein Transport
PubMed: 29684214
DOI: 10.1093/pcp/pcy083 -
Proceedings of the National Academy of... Feb 2021Mitochondrial protein import requires outer membrane receptors that evolved independently in different lineages. Here we used quantitative proteomics and in vitro...
Mitochondrial protein import requires outer membrane receptors that evolved independently in different lineages. Here we used quantitative proteomics and in vitro binding assays to investigate the substrate preferences of ATOM46 and ATOM69, the two mitochondrial import receptors of The results show that ATOM46 prefers presequence-containing, hydrophilic proteins that lack transmembrane domains (TMDs), whereas ATOM69 prefers presequence-lacking, hydrophobic substrates that have TMDs. Thus, the ATOM46/yeast Tom20 and the ATOM69/yeast Tom70 pairs have similar substrate preferences. However, ATOM46 mainly uses electrostatic, and Tom20 hydrophobic, interactions for substrate binding. In vivo replacement of ATOM46 by yeast Tom20 did not restore import. However, replacement of ATOM69 by the recently discovered Tom36 receptor of hydrogenosomes, while not allowing for growth, restored import of a large subset of trypanosomal proteins that lack TMDs. Thus, even though ATOM69 and Tom36 share the same domain structure and topology, they have different substrate preferences. The study establishes complementation experiments, combined with quantitative proteomics, as a highly versatile and sensitive method to compare in vivo preferences of protein import receptors. Moreover, it illustrates the role determinism and contingencies played in the evolution of mitochondrial protein import receptors.
Topics: Animals; Carrier Proteins; Evolution, Molecular; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Protein Binding; Protein Precursors; Protein Transport; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Trypanosoma brucei brucei
PubMed: 33526678
DOI: 10.1073/pnas.2017774118 -
Seminars in Cell & Developmental Biology Apr 2018Mitochondria are fundamental structures that fulfil important and diverse functions within cells, including cellular respiration and iron-sulfur cluster biogenesis.... (Review)
Review
Mitochondria are fundamental structures that fulfil important and diverse functions within cells, including cellular respiration and iron-sulfur cluster biogenesis. Mitochondrial function is reliant on the organelles proteome, which is maintained and adjusted depending on cellular requirements. The majority of mitochondrial proteins are encoded by nuclear genes and must be trafficked to, and imported into the organelle following synthesis in the cytosol. These nuclear-encoded mitochondrial precursors utilise dynamic and multimeric translocation machines to traverse the organelles membranes and be partitioned to the appropriate mitochondrial subcompartment. Yeast model systems have been instrumental in establishing the molecular basis of mitochondrial protein import machines and mechanisms, however unique players and mechanisms are apparent in higher eukaryotes. Here, we review our current knowledge on mitochondrial protein import in human cells and how dysfunction in these pathways can lead to disease.
Topics: Humans; Mitochondrial Proteins; Protein Transport
PubMed: 28765093
DOI: 10.1016/j.semcdb.2017.07.028 -
Biochimica Et Biophysica Acta May 2016Peroxisomes are highly dynamic organelles that can rapidly change in size, abundance, and protein content in response to alterations in nutritional and other... (Review)
Review
Peroxisomes are highly dynamic organelles that can rapidly change in size, abundance, and protein content in response to alterations in nutritional and other environmental conditions. These dynamic changes in peroxisome features, referred to as peroxisome dynamics, rely on the coordinated action of several processes of peroxisome biogenesis. Revealing the regulatory mechanisms of peroxisome dynamics is an emerging theme in cell biology. These mechanisms are inevitably linked to and synchronized with the biogenesis and degradation of peroxisomes. To date, the key players and basic principles of virtually all steps in the peroxisomal life cycle are known, but regulatory mechanisms remained largely elusive. A number of recent studies put the spotlight on reversible protein phosphorylation for the control of peroxisome dynamics and highlighted peroxisomes as hubs for cellular signal integration and regulation. Here, we will present and discuss the results of several studies performed using yeast and mammalian cells that convey a sense of the impact protein phosphorylation may have on the modulation of peroxisome dynamics by regulating peroxisomal matrix and membrane protein import, proliferation, inheritance, and degradation. We further put forward the idea to make use of current data on phosphorylation sites of peroxisomal and peroxisome-associated proteins reported in advanced large-scale phosphoproteomic studies.
Topics: Animals; Autophagy; Gene Expression Regulation; Glycerol-3-Phosphate Dehydrogenase (NAD+); Humans; Membrane Proteins; Membrane Transport Proteins; Mice; Organelle Biogenesis; Peroxisomal Targeting Signal 2 Receptor; Peroxisome-Targeting Signal 1 Receptor; Peroxisomes; Phosphorylation; Protein Isoforms; Protein Transport; Receptors, Cytoplasmic and Nuclear; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction
PubMed: 26775584
DOI: 10.1016/j.bbamcr.2015.12.022 -
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 -
International Review of Cell and... 2017Eukaryotic organisms are defined by their endomembrane system and various organelles. The membranes that define these organelles require complex protein sorting and... (Review)
Review
Eukaryotic organisms are defined by their endomembrane system and various organelles. The membranes that define these organelles require complex protein sorting and molecular machines that selectively mediate the import of proteins from the cytosol to their functional location inside the organelle. The plastid possibly represents the most complex system of protein sorting, requiring many different translocons located in the three membranes found in this organelle. Despite having a small genome of its own, the vast majority of plastid-localized proteins is nuclear encoded and must be posttranslationally imported from the cytosol. These proteins are encoded as a larger molecular weight precursor that contains a special "zip code," a targeting sequence specific to the intended final destination of a given protein. The "zip code" is located at the precursor N-terminus, appropriately called a transit peptide (TP). We aim to provide an overview of plastid trafficking with a focus on the mechanism and regulation of the general import pathway, which serves as a central import hub for thousands of proteins that function in the plastid. We extend comparative analysis of plant proteomes to develop a better understanding of the evolution of TPs and differential TP recognition. We also review alternate import pathways, including vesicle-mediated trafficking, dual targeting, and import of signal-anchored and tail-anchored proteins.
Topics: Amino Acid Sequence; Models, Biological; Plant Proteins; Plastids; Protein Transport; Symbiosis
PubMed: 28215533
DOI: 10.1016/bs.ircmb.2016.09.006