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International Journal of Biological... 2022Protein palmitoylation is an increasingly investigated form of post-translational lipid modification that affects protein localization, accumulation, secretion and... (Review)
Review
Protein palmitoylation is an increasingly investigated form of post-translational lipid modification that affects protein localization, accumulation, secretion and function. Recently, emerging findings have revealed that protein palmitoylation is crucial for many tumor-related signaling pathways, such as EGFR, RAS, PD-1/PD-L1 signaling, affecting the occurrence, progression and therapeutic response of tumors. Protein palmitoylation and its modifying enzymes, including palmitoylases and depalmitoylases, are expected to be new targets for effective tumor treatment. Recognizing the significance of palmitoylation modification on protein stability, localization and downstream signal regulation, this review focuses on the regulatory roles of protein palmitoylation and its modifying enzymes in tumor cell signal transduction, aiming to bring new ideas for effective cancer prevention and treatment.
Topics: Lipoylation; Neoplasms; Protein Processing, Post-Translational; Protein Transport; Signal Transduction
PubMed: 35637973
DOI: 10.7150/ijbs.72244 -
Nature Communications May 2023Retromer controls cellular homeostasis through regulating integral membrane protein sorting and transport and by controlling maturation of the endo-lysosomal network....
Retromer controls cellular homeostasis through regulating integral membrane protein sorting and transport and by controlling maturation of the endo-lysosomal network. Retromer dysfunction, which is linked to neurodegenerative disorders including Parkinson's and Alzheimer's diseases, manifests in complex cellular phenotypes, though the precise nature of this dysfunction, and its relation to neurodegeneration, remain unclear. Here, we perform an integrated multi-omics approach to provide precise insight into the impact of Retromer dysfunction on endo-lysosomal health and homeostasis within a human neuroglioma cell model. We quantify widespread changes to the lysosomal proteome, indicative of broad lysosomal dysfunction and inefficient autophagic lysosome reformation, coupled with a reconfigured cell surface proteome and secretome reflective of increased lysosomal exocytosis. Through this global proteomic approach and parallel transcriptomic analysis, we provide a holistic view of Retromer function in regulating lysosomal homeostasis and emphasise its role in neuroprotection.
Topics: Humans; Neuroprotection; Multiomics; Proteome; Proteomics; Endosomes; Protein Transport; Lysosomes
PubMed: 37248224
DOI: 10.1038/s41467-023-38719-8 -
Microbiological Research Oct 2019T. gondii is a major opportunistic pathogen chronically infecting nearly one third of the world's population. Due to the high infection and mortality rates in... (Review)
Review
T. gondii is a major opportunistic pathogen chronically infecting nearly one third of the world's population. Due to the high infection and mortality rates in immunocompromised patients and newborns, the extent or magnitude of T. gondii pathogenesis is determined mainly by host-pathogen interactions. T. gondii utilizes specialized secretory proteins to modify host cellular factors and facilitate invasion and replication. This review provides update on the recent progress in this field of research with particular emphasis on the T. gondii secretory proteins and their role in invasion and pathogenesis.
Topics: Animals; Host-Parasite Interactions; Humans; Life Cycle Stages; Protein Transport; Protozoan Proteins; Toxoplasma; Toxoplasmosis
PubMed: 31421715
DOI: 10.1016/j.micres.2019.06.003 -
Nature Cell Biology Jun 2022Mechanical force controls fundamental cellular processes in health and disease, and increasing evidence shows that the nucleus both experiences and senses applied...
Mechanical force controls fundamental cellular processes in health and disease, and increasing evidence shows that the nucleus both experiences and senses applied forces. Such forces can lead to the nuclear translocation of proteins, but whether force controls nucleocytoplasmic transport, and how, remains unknown. Here we show that nuclear forces differentially control passive and facilitated nucleocytoplasmic transport, setting the rules for the mechanosensitivity of shuttling proteins. We demonstrate that nuclear force increases permeability across nuclear pore complexes, with a dependence on molecular weight that is stronger for passive than for facilitated diffusion. Owing to this differential effect, force leads to the translocation of cargoes into or out of the nucleus within a given range of molecular weight and affinity for nuclear transport receptors. Further, we show that the mechanosensitivity of several transcriptional regulators can be both explained by this mechanism and engineered exogenously by introducing appropriate nuclear localization signals. Our work unveils a mechanism of mechanically induced signalling, probably operating in parallel with others, with potential applicability across signalling pathways.
Topics: Active Transport, Cell Nucleus; Cell Nucleus; Nuclear Pore; Protein Transport; Receptors, Cytoplasmic and Nuclear
PubMed: 35681009
DOI: 10.1038/s41556-022-00927-7 -
Autophagy Apr 2023The endosomal system maintains cellular homeostasis by coordinating multiple vesicular trafficking events, and the retromer complex plays a critical role in endosomal...
The endosomal system maintains cellular homeostasis by coordinating multiple vesicular trafficking events, and the retromer complex plays a critical role in endosomal cargo recognition and sorting. Here, we demonstrate an essential role for the small GTPase RAB21 in regulating retromer-mediated recycling of the glucose transporter SLC2A1/GLUT1 and macroautophagy/autophagy. RAB21 depletion mis-sorts SLC2A1 to lysosomes and affects glucose uptake, thereby activating the AMPK-ULK1 pathway to increase autophagic flux. RAB21 depletion also increases lysosome function. Notably, RAB21 depletion does not overtly affect retrograde transport of IGF2R/CI-M6PR or WLS from endosomes to the trans-Golgi network. We speculate that RAB21 regulates fission of retromer-decorated endosomal tubules, as RAB21 depletion causes accumulation of the SNX27-containing retromer complex on enlarged endosomes at the perinuclear region. Functionally, RAB21 depletion sensitizes cancer cells to energy stress and inhibits tumor growth in vivo, suggesting an oncogenic role for RAB21. Overall, our study illuminates the role of RAB21 in regulating endosomal dynamics and maintaining cellular energy homeostasis and suggests RAB21 as a potential metabolic target for cancer therapy.
Topics: Vesicular Transport Proteins; Autophagy; Glucose Transporter Type 1; Protein Transport; Endosomes; Homeostasis
PubMed: 35993307
DOI: 10.1080/15548627.2022.2114271 -
Biomolecules Jun 2022Primary cilia are non-motile organelles associated with the cell cycle, which can be found in most vertebrate cell types. Cilia formation occurs through a process called... (Review)
Review
Primary cilia are non-motile organelles associated with the cell cycle, which can be found in most vertebrate cell types. Cilia formation occurs through a process called ciliogenesis, which involves several mechanisms including planar cell polarity (PCP) and the Hedgehog (Hh) signaling pathway. Some gene complexes, such as BBSome or CPLANE (ciliogenesis and planar polarity effector), have been linked to ciliogenesis. CPLANE complex is composed of , and , which bind to and for cilia formation. Defects in these genes have been linked to a malfunction of intraflagellar transport and defects in the planar cell polarity, as well as defective activation of the Hedgehog signalling pathway. These faults lead to defective cilium formation, resulting in ciliopathies, including orofacial-digital syndrome (OFDS) and Bardet-Biedl syndrome (BBS). Considering the close relationship, between the CPLANE complex and cilium formation, it can be expected that defects in the genes that encode subunits of the CPLANE complex may be related to other ciliopathies.
Topics: Cell Polarity; Cilia; Ciliopathies; Hedgehog Proteins; Humans; Protein Transport
PubMed: 35740972
DOI: 10.3390/biom12060847 -
Developmental Cell Dec 2023Endoplasmic reticulum (ER)-phagy is crucial to regulate the function and homeostasis of the ER via lysosomal degradation, but how it is initiated is unclear. Here we...
Endoplasmic reticulum (ER)-phagy is crucial to regulate the function and homeostasis of the ER via lysosomal degradation, but how it is initiated is unclear. Here we discover that Z-AAT, a disease-causing mutant of α1-antitrypsin, induces noncanonical ER-phagy at ER exit sites (ERESs). Accumulation of misfolded Z-AAT at the ERESs impairs coat protein complex II (COPII)-mediated ER-to-Golgi transport and retains V0 subunits that further assemble V-ATPase at the arrested ERESs. V-ATPase subsequently recruits ATG16L1 onto ERESs to mediate in situ lipidation of LC3C. FAM134B-II is then recruited by LC3C via its LIR motif and elicits ER-phagy leading to efficient lysosomal degradation of Z-AAT. Activation of this ER-phagy mediated by the V-ATPase-ATG16L1-LC3C axis (EVAC) is also triggered by blocking ER export. Our findings identify a pathway which switches COPII-mediated transport to lysosomal degradation for ER quality control.
Topics: Adenosine Triphosphatases; Lysosomes; Protein Transport; Golgi Apparatus; Endoplasmic Reticulum; Autophagy
PubMed: 37922908
DOI: 10.1016/j.devcel.2023.10.007 -
Frontiers in Cellular and Infection... 2019
Topics: Bacteria; Bacterial Proteins; Bacterial Secretion Systems; Host-Pathogen Interactions; Membrane Transport Proteins; Protein Transport
PubMed: 32039049
DOI: 10.3389/fcimb.2019.00473 -
Molecular Plant Aug 2021Drought is the leading environmental threat affecting crop productivity, and plants have evolved a series of mechanisms to adapt to drought stress. The FT-interacting...
Drought is the leading environmental threat affecting crop productivity, and plants have evolved a series of mechanisms to adapt to drought stress. The FT-interacting proteins (FTIPs) and phosphatidylethanolamine-binding proteins (PEBPs) play key roles in developmental processes, whereas their roles in the regulation of stress response are still largely unknown. Here, we report that OsFTIP1 negatively regulates drought response in rice. We showed that OsFTIP1 interacts with rice MOTHER OF FT AND TFL1 (OsMFT1), a PEBP that promotes rice tolerance to drought treatment. Further studies discovered that OsMFT1 interacts with two key drought-related transcription factors, OsbZIP66 and OsMYB26, regulating their binding capacity on drought-related genes and thereby enhancing drought tolerance in rice. Interestingly, we found that OsFTIP1 impedes the nucleocytoplasmic translocation of OsMFT1, implying that dynamic modulation of drought-responsive genes by the OsMFT1-OsMYB26 and OsMFT1-OsbZIP66 complexes is integral to OsFTIP1-modulated nuclear accumulation of OsMFT1. Our findings also suggest that OsMFT1 might act as a hitherto unknown nucleocytoplasmic trafficking signal that regulates drought tolerance in rice in response to environmental signals.
Topics: Adaptation, Physiological; Droughts; Gene Expression Regulation, Plant; Oryza; Plant Proteins; Plants, Genetically Modified; Protein Transport; Stress, Physiological; Transcription Factors
PubMed: 33962060
DOI: 10.1016/j.molp.2021.05.001 -
Advances in Experimental Medicine and... 2020Although originally characterized as a cytoplasmic protein, myosin of various classes also performs key functions in the nucleus. We review the data concerning the... (Review)
Review
Although originally characterized as a cytoplasmic protein, myosin of various classes also performs key functions in the nucleus. We review the data concerning the nuclear localization, mechanism of entry, and functional interactions of myosin I, II, V, VI, X, XVI, and XVIII. To date, the first-characterized "nuclear myosin I" (or, in the prevailing nomenclature, myosin IC isoform B) remains the best-studied nuclear myosin, although results are rapidly accumulating that illuminate the roles of other myosin classes, and an outline of a unified picture of myosin functions in the nucleus is beginning to emerge. Reflecting the state of knowledge in this field, the review concentrates on the mechanisms mediating and regulating import of myosin IC into the nucleus and its role, alongside myosin V and VI, in transcription. Myosin functions in chromatin dynamics, epigenetic mechanisms, intranuclear motility, and nuclear export of RNA and protein are also addressed. Partners and regulators of myosin, such as nuclear actin, kinases, and phosphatases are briefly covered. Problem areas are identified and testable hypotheses are offered with an aim of focusing the research efforts on overcoming the gaps on the way toward a systems-level understanding of processes involving nuclear myosins and their place in cell physiology as a whole.
Topics: Actins; Active Transport, Cell Nucleus; Cell Nucleus; Humans; Myosins; Phosphoric Monoester Hydrolases; Phosphotransferases; Protein Transport
PubMed: 32451861
DOI: 10.1007/978-3-030-38062-5_10