-
Advances in Experimental Medicine and... 2023Aquaporins (AQPs) mediate water flux between the four distinct water compartments in the central nervous system (CNS). In the present chapter, we mainly focus on the...
Aquaporins (AQPs) mediate water flux between the four distinct water compartments in the central nervous system (CNS). In the present chapter, we mainly focus on the expression and function of the nine AQPs expressed in the CNS, which include five members of aquaporin subfamily: AQP1, AQP4, AQP5, AQP6, and AQP8; three members of aquaglyceroporin subfamily: AQP3, AQP7, and AQP9; and one member of superaquaporin subfamily: AQP11. In addition, AQP1, AQP2, and AQP4 expressed in the peripheral nervous system are also reviewed. AQP4, the predominant water channel in the CNS, is involved both in the astrocyte swelling of cytotoxic edema and the resolution of vasogenic edema and is of pivotal importance in the pathology of brain disorders such as neuromyelitis optica, brain tumors, and neurodegenerative disorders. Moreover, AQP4 has been demonstrated as a functional regulator of recently discovered glymphatic system that is a main contributor to clearance of toxic macromolecule from the brain. Other AQPs are also involved in a variety of important physiological and pathological process in the brain. It has been suggested that AQPs could represent an important target in treatment of brain disorders like cerebral edema. Future investigations are necessary to elucidate the pathological significance of AQPs in the CNS.
Topics: Humans; Aquaporin 2; Aquaporins; Central Nervous System; Brain Neoplasms; Brain; Water
PubMed: 36717489
DOI: 10.1007/978-981-19-7415-1_7 -
Proceedings of the National Academy of... Feb 2024Cancer invasion and metastasis are known to be potentiated by the expression of aquaporins (AQPs). Likewise, the expression levels of AQPs have been shown to be...
Cancer invasion and metastasis are known to be potentiated by the expression of aquaporins (AQPs). Likewise, the expression levels of AQPs have been shown to be prognostic for survival in patients and have a role in tumor growth, edema, angiogenesis, and tumor cell migration. Thus, AQPs are key players in cancer biology and potential targets for drug development. Here, we present the single-particle cryo-EM structure of human AQP7 at 3.2-Å resolution in complex with the specific inhibitor compound Z433927330. The structure in combination with MD simulations shows that the inhibitor binds to the endofacial side of AQP7. In addition, cancer cells treated with Z433927330 show reduced proliferation. The data presented here serve as a framework for the development of AQP inhibitors.
Topics: Humans; Aquaporins; Neoplasms; Aquaporin 1
PubMed: 38319972
DOI: 10.1073/pnas.2319682121 -
International Journal of Molecular... Aug 2022Spanish or Spanish-speaking scientists represent a remarkably populated group within the scientific community studying pore-forming proteins. Some of these scientists,... (Review)
Review
Spanish or Spanish-speaking scientists represent a remarkably populated group within the scientific community studying pore-forming proteins. Some of these scientists, ourselves included, focus on the study of actinoporins, a fascinating group of metamorphic pore-forming proteins produced within the venom of several sea anemones. These toxic proteins can spontaneously transit from a water-soluble fold to an integral membrane ensemble because they specifically recognize sphingomyelin in the membrane. Once they bind to the bilayer, they subsequently oligomerize into a pore that triggers cell-death by osmotic shock. In addition to sphingomyelin, some actinoporins are especially sensible to some other membrane components such as cholesterol. Our group from Universidad Complutense of Madrid has focused greatly on the role played by sterols in this water-membrane transition, a question which still remains only partially solved and constitutes the main core of the article below.
Topics: Animals; Cholesterol; Cnidarian Venoms; Porins; Sea Anemones; Sphingomyelins; Water
PubMed: 35955905
DOI: 10.3390/ijms23158771 -
Nature Microbiology Aug 2021Fusobacterium nucleatum, long known as a constituent of the oral microflora, has recently garnered renewed attention for its association with several different human...
Fusobacterium nucleatum, long known as a constituent of the oral microflora, has recently garnered renewed attention for its association with several different human cancers. The growing interest in this emerging cancer-associated bacterium contrasts with a paucity of knowledge about its basic gene expression features and physiological responses. As fusobacteria lack all established small RNA-associated proteins, post-transcriptional networks in these bacteria are also unknown. In the present study, using differential RNA-sequencing, we generate high-resolution global RNA maps for five clinically relevant fusobacterial strains-F. nucleatum subspecies nucleatum, animalis, polymorphum and vincentii, as well as F. periodonticum-for early, mid-exponential growth and early stationary phase. These data are made available in an online browser, and we use these to uncover fundamental aspects of fusobacterial gene expression architecture and a suite of non-coding RNAs. Developing a vector for functional analysis of fusobacterial genes, we discover a conserved fusobacterial oxygen-induced small RNA, FoxI, which serves as a post-transcriptional repressor of the major outer membrane porin FomA. Our findings provide a crucial step towards delineating the regulatory networks enabling F. nucleatum adaptation to different environments, which may elucidate how these bacteria colonize different compartments of the human body.
Topics: Bacterial Proteins; Fusobacterium Infections; Fusobacterium nucleatum; Humans; Neoplasms; Porins; RNA, Bacterial
PubMed: 34239075
DOI: 10.1038/s41564-021-00927-7 -
Nature Sep 2023Many animal- and plant-pathogenic bacteria use a type III secretion system to deliver effector proteins into host cells. Elucidation of how these effector proteins...
Many animal- and plant-pathogenic bacteria use a type III secretion system to deliver effector proteins into host cells. Elucidation of how these effector proteins function in host cells is critical for understanding infectious diseases in animals and plants. The widely conserved AvrE-family effectors, including DspE in Erwinia amylovora and AvrE in Pseudomonas syringae, have a central role in the pathogenesis of diverse phytopathogenic bacteria. These conserved effectors are involved in the induction of 'water soaking' and host cell death that are conducive to bacterial multiplication in infected tissues. However, the exact biochemical functions of AvrE-family effectors have been recalcitrant to mechanistic understanding for three decades. Here we show that AvrE-family effectors fold into a β-barrel structure that resembles bacterial porins. Expression of AvrE and DspE in Xenopus oocytes results in inward and outward currents, permeability to water and osmolarity-dependent oocyte swelling and bursting. Liposome reconstitution confirmed that the DspE channel alone is sufficient to allow the passage of small molecules such as fluorescein dye. Targeted screening of chemical blockers based on the predicted pore size (15-20 Å) of the DspE channel identified polyamidoamine dendrimers as inhibitors of the DspE/AvrE channels. Notably, polyamidoamines broadly inhibit AvrE and DspE virulence activities in Xenopus oocytes and during E. amylovora and P. syringae infections. Thus, we have unravelled the biochemical function of a centrally important family of bacterial effectors with broad conceptual and practical implications in the study of bacterial pathogenesis.
Topics: Animals; Bacterial Proteins; Cell Death; Fluorescein; Liposomes; Oocytes; Plant Cells; Plant Diseases; Porins; Protein Folding; Solutions; Water; Xenopus laevis; Osmolar Concentration
PubMed: 37704725
DOI: 10.1038/s41586-023-06531-5 -
Biochemical Society Transactions Oct 2019Mitochondria are essential eukaryotic organelles responsible for primary cellular energy production. Biogenesis, maintenance, and functions of mitochondria require... (Review)
Review
Mitochondria are essential eukaryotic organelles responsible for primary cellular energy production. Biogenesis, maintenance, and functions of mitochondria require correct assembly of resident proteins and lipids, which require their transport into and within mitochondria. Mitochondrial normal functions also require an exchange of small metabolites between the cytosol and mitochondria, which is primarily mediated by a metabolite channel of the outer membrane (OM) called porin or voltage-dependent anion channel. Here, we describe recently revealed novel roles of porin in the mitochondrial protein and lipid transport. First, porin regulates the formation of the mitochondrial protein import gate in the OM, the translocase of the outer membrane (TOM) complex, and its dynamic exchange between the major form of a trimer and the minor form of a dimer. The TOM complex dimer lacks a core subunit Tom22 and mediates the import of a subset of mitochondrial proteins while the TOM complex trimer facilitates the import of most other mitochondrial proteins. Second, porin interacts with both a translocating inner membrane (IM) protein like a carrier protein accumulated at the small TIM chaperones in the intermembrane space and the TIM22 complex, a downstream translocator in the IM for the carrier protein import. Porin thereby facilitates the efficient transfer of carrier proteins to the IM during their import. Third, porin facilitates the transfer of lipids between the OM and IM and promotes a back-up pathway for the cardiolipin synthesis in mitochondria. Thus, porin has roles more than the metabolite transport in the protein and lipid transport into and within mitochondria, which is likely conserved from yeast to human.
Topics: Biological Transport; Cell Cycle; Lipid Metabolism; Mitochondria; Mitochondrial Proteins; Porins
PubMed: 31670371
DOI: 10.1042/BST20190153 -
Advances in Experimental Medicine and... 2023Aquaporins (AQPs) are present not only in three domains of life, bacteria, eukaryotes, and archaea, but also in viruses. With the accumulating arrays of AQP superfamily,...
Aquaporins (AQPs) are present not only in three domains of life, bacteria, eukaryotes, and archaea, but also in viruses. With the accumulating arrays of AQP superfamily, the evolutional relationship has attracted much attention with multiple publications on "the genome-wide identification and phylogenetic analysis" of AQP superfamily. A pair of NPA boxes forming a pore is highly conserved throughout the evolution and renders key residues for the classification of AQP superfamily into four groups: AQP1-like, AQP3-like, AQP8-like, and AQP11-like. The complexity of AQP family has mostly been achieved in nematodes and subsequent evolution has been directed toward increasing the number of AQPs through whole-genome duplications (WGDs) to extend the tissue specific expression and regulation. The discovery of the intracellular AQP (iAQP: AQP8-like and AQP11-like) and substrate transports by the plasma membrane AQP (pAQP: AQP1-like and AQP3-like) have accelerated the AQP research much more toward the transport of substrates with complex profiles. This evolutionary overview based on a simple classification of AQPs into four subfamilies will provide putative structural, functional, and localization information and insights into the role of AQP as well as clues to understand the complex diversity of AQP superfamily.
Topics: Phylogeny; Genome; Aquaporins
PubMed: 36717488
DOI: 10.1007/978-981-19-7415-1_6 -
Nature Dec 2023Gram-negative antibiotic development has been hindered by a poor understanding of the types of compounds that can accumulate within these bacteria. The presence of...
Gram-negative antibiotic development has been hindered by a poor understanding of the types of compounds that can accumulate within these bacteria. The presence of efflux pumps and substrate-specific outer-membrane porins in Pseudomonas aeruginosa renders this pathogen particularly challenging. As a result, there are few antibiotic options for P. aeruginosa infections and its many porins have made the prospect of discovering general accumulation guidelines seem unlikely. Here we assess the whole-cell accumulation of 345 diverse compounds in P. aeruginosa and Escherichia coli. Although certain positively charged compounds permeate both bacterial species, P. aeruginosa is more restrictive compared to E. coli. Computational analysis identified distinct physicochemical properties of small molecules that specifically correlate with P. aeruginosa accumulation, such as formal charge, positive polar surface area and hydrogen bond donor surface area. Mode of uptake studies revealed that most small molecules permeate P. aeruginosa using a porin-independent pathway, thus enabling discovery of general P. aeruginosa accumulation trends with important implications for future antibiotic development. Retrospective antibiotic examples confirmed these trends and these discoveries were then applied to expand the spectrum of activity of a gram-positive-only antibiotic, fusidic acid, into a version that demonstrates a dramatic improvement in antibacterial activity against P. aeruginosa. We anticipate that these discoveries will facilitate the design and development of high-permeating antipseudomonals.
Topics: Anti-Bacterial Agents; Escherichia coli; Microbial Sensitivity Tests; Porins; Pseudomonas aeruginosa; Retrospective Studies; Static Electricity; Hydrogen Bonding; Fusidic Acid; Drug Design
PubMed: 37993720
DOI: 10.1038/s41586-023-06760-8 -
Reviews in Medical Virology Jul 2023Viruses control the host cell by exploiting its molecular machinery to facilitate viral replication and propagation. Understanding different viral mechanisms and... (Review)
Review
Viruses control the host cell by exploiting its molecular machinery to facilitate viral replication and propagation. Understanding different viral mechanisms and biochemical pathways is crucial for finding promising therapeutic solutions to viral infections. The mitochondrion is a vital organelle targeted by various types of viruses. More specifically, viruses interact with the voltage-dependent anion channel (VDAC), a porin protein found in the outer mitochondrial membrane. VDAC controls metabolite flux, regulates reactive oxygen species production, and promotes mitochondrial-mediated apoptosis by releasing pro-apoptotic proteins. Hence, a common pathogenic strategy used by many viruses seems to exploit natural pathways that VDAC regulates. This review aims to address the inhibition and enhancement roles of VDAC in viral pathogenesis and outlines multiple links and interactions between VDAC and viral proteins as potential antiviral targets.
Topics: Humans; Voltage-Dependent Anion Channels; Mitochondria; Apoptosis; Viral Proteins; Virus Diseases
PubMed: 37170417
DOI: 10.1002/rmv.2453 -
Trends in Microbiology Jun 2022The cell envelope is essential for survival and adaptation of bacteria. Bacterial membrane proteins include the major porins that mediate the influx of nutrients and... (Review)
Review
The cell envelope is essential for survival and adaptation of bacteria. Bacterial membrane proteins include the major porins that mediate the influx of nutrients and several classes of antimicrobial drugs. Consequently, membrane remodelling is closely linked to antimicrobial resistance (AMR). Knowledge of bacterial membrane protein biogenesis and turnover underpins our understanding of bacterial membrane remodelling and the consequences that this process have in the evolution of AMR phenotypes. At the population level, the evolution of phenotypes is a reversible process, and we can use these insights to deploy evolutionary principles to resensitize bacteria to existing antimicrobial drugs. In our opinion, fundamental knowledge is opening a new way of thinking towards sustainable solutions to the mounting crisis in AMR. Here we discuss what is known about outer-membrane remodelling in bacteria and how the process could be targeted as a means to restore sensitivity to antimicrobial drugs. Bacteriophages are highlighted as a powerful means to exert this control over membrane remodelling but they require careful selection so as to reverse, and not exacerbate, AMR phenotypes.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Porins
PubMed: 34872824
DOI: 10.1016/j.tim.2021.11.002