The interactions between pathogens and host cells and the way by which the immune response is modulated during this process ultimately dictate the fate of infection. Host phagocytes exposed to Mycobacterium tuberculosis (M. tuberculosis) sense microbial-associated molecular patterns and activate a series of signaling pathways. In this setting, activation of the nuclear factor κB (NF-κB) initiates transcription of several key genes involved in orchestration of antimycobacterial effector functions. This review describes these major pathways that govern the outcome of host phagocytes infected with M. tuberculosis. Furthermore, we highlight evidence of how M. tuberculosis modulates activation of NF-κB pathways to evade the host antimycobacterial defense.
‘Proteinopathy’ refers to a class of diseases where the aggregation of misfolded or non-native proteins/inclusion bodies is identified to be the underlying cause. Most neurodegenerative diseases feature such non-native protein aggregates or inclusion bodies. Over 4 decades of research on Alzheimer disease and various other neurodegenerative diseases has highlighted the importance of an articulate and precise proteostasis machinery in protein quality control. This proteostasis machinery exists both within and outside the cells. A great number of studies have elucidated the role of intracellular chaperones in guiding the process of folding and clearance of native and non-native proteins. However, our idea about the mechanism and processes involved in regulation of proteostasis by extracellular chaperones is still largely unknown. In addition, the process of proteostasis differs within the cell types; for example, different populations of neuronal cells are known for selective vulnerability to physiological stress. This review focusses on the extracellular chaperones, their role in protein quality control, and their effect on neuronal structure, function, and survivability.
Primary cilium, a small, antenna-like, microtubule (MT)-based extracellular organelle, which extends from the surface of all types of human cells, has important roles in various cellular functions, including planar cell polarity, cell growth, cell cycle, cell migration, transactivation, and immune response. Primary cilium-mediated signaling cascades are initiated by chemosensing environmental signals, such as growth factors and morphogens that activate ciliary receptor-mediated signal transduction, or by mechanosensing of fluid flow followed by induction of intracellular Ca²⁺ flux. Owing to the versatile tools that cilia have, enabling various cellular functions, ciliary dysfunction causes several cilium-related human disorders such as ciliopathies. Here, we focus on the structure and biogenesis of primary cilium and discuss primary cilium-mediated crosstalk of the molecular mechanisms of signaling cascades in ciliogenesis, tumorigenesis, and senescence.
Epithelial–stromal interaction 1 (EPSTI1) was initially identified as an induced gene in breast cancer epithelial cells by cocultured stromal fibroblasts. This discovery led to further investigation and understanding of the role of EPSTI1 in cancer. Aberrant elevation of EPSTI1 occurs primarily in invasive breast cancer epithelial cells. Forced overexpression of EPSTI1 in noninvasive cancer cells can substitute for the stromal fibroblasts. EPSTI1 was further implicated in cancer by our most recent study that identified it as one of the few most upregulated genes in human breast cancer by Kruppel-like factor 8 (KLF8), a pro-cancerous transcription factor in many cancer types. Our study also demonstrated that EPSTI1 interacts with valosin-containing protein to promote the degradation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) inhibitor alpha, leading to the activation and nuclear translocation of NF- κB. Additionally, EPSTI1 was shown to inhibit apoptosis by inactivating caspase 8. Studies on hepatitis C and E viruses have indicated that EPSTI1 plays a role in inhibition of the viral replication by promoting the expression of protein kinase R or protein kinase RNA-activated, a viral response gene, suggesting a role of EPSTI1 in immune response. Interestingly, in addition to transducing stromal signals, EPSTI1 has been implicated in immune privilege and autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and histiocytic necrotizing lymphadenitis. This review seeks to comb EPSTI1-related studies as it was cloned a dozen years ago with a particular focus on the mechanisms of its regulation and signaling, as well as its potential roles in the diseases.
Cortisol production is normally under the regulation of adrenocorticotropic hormone (ACTH). Hypercortisolism or Cushing’s syndrome, characterized by excessive cortisol levels, may be caused by ACTH-independent mechanisms. The present work aims to review the current knowledge on ACTH-independent mechanisms through aberrant expression of hormone receptors in adrenal tumors and adrenocortical hyperplasia. In particular, the effects of epinephrine, norepinephrine, serotonin, arginine vasopressin, and gastric inhibitory polypeptide are discussed.
Currently, the biologic sciences are a Tower of Babel, having become so highly specialized that one discipline cannot effectively communicate with another. A mechanism for evolution that integrates development and physiologic homeostasis phylogenetically has been identified-cell-cell interactions. By reducing this process to ligand-receptor interactions and their intermediate down-stream signaling partners, it is possible, for example, to envision the functional homologies between such seemingly disparate structures and functions as the lung alveolus and kidney glomerulus, the skin and brain, or the skin and lung. For example, by showing the continuum of the lung phenotype for gas exchange at the cell-molecular level, being selected for increased surface area by augmenting lung surfactant production and function in lowering surface tension, we have determined an unprecedented structural-functional continuum from proximate to ultimate causation in evolution. It is maintained that tracing the changes in structure and function that have occurred over both the short-term history of the organism (as ontogeny), and the long-term history of the organism (as phylogeny), and how the mechanisms shared in common can account for both biologic stability and novelty, will provide the key to understanding the mechanisms of evolution. We need to better understand evolution from its unicellular origins as the Big Bang of biology.
It is becoming increasingly clear that communication between cells is carried out not only by the signaling molecules themselves, but also by many contextual and positional cues that arise from the way the signal is distributed and presented to the receptor. Many cells express transmembrane growth factors that use their extracellular domain for signaling to cells connected by adhesion. Some of these growth factors can also be receptors for a reverse signal from the adhesion partner. Secreted growth factors or their receptors can engage in contact-dependent signaling by associating with extracellular matrix (ECM) components and integrins. Signaling molecules can also reach cells at a distance via cytonemes that contact and activate the target cell through synapse-like structures.
Protein-protein interactions play a pivotal role in both inter- and intra-cellular signaling. Identification of signaling protein complexes can thus shed important new insights into cell communications. We developed a parallel affinity precipitation protocol to overcome the disadvantages of the tandem affinity purification procedure, such as the potential disruption of target protein conformation, subcellular localization or function by epitope tags, the potential need of large amounts of cell culture or generation of stable cell lines, and relatively long duration the two-step precipitation takes. This new simplified assay of protein interaction is quick, economic and specific. This paper describes the details in the design and method of the assay.
Elevated levels of plasminogen activator inhibitor type-1 (PAI-1) often occur in concert with the conversion of non-motile epithelial elements into a more migratory phenotype. While essential during embryonic development, this restructuring process, referred to as epithelial-to-mesenchymal-transition (EMT) is limited in the adult organism, occurring normally during wound repair or more atypically in tumor progression. Cell motility, the focal point of EMT, requires the coordinate regulation of multiple mechanisms which ensure proper communication between cell surface receptors and the extracellular environment. PAI-1, through multifaceted interactions with both extracellular matrix (ECM) and cell surface constituents plays a critical role in modulating many of these events. This review focuses on the complex role of PAI-1 in the cellular motile program.
Plasminogen activator inhibitor-1 (PAI-1) has been found to affect a number of important cell processes and therefore abnormal expression of PAI-1 has been associated with a number of diseases and disorders. Understanding the transactivation of PAI-1 may result in identifying novel therapeutic targets.
In the post-genomic era the complex problem of evolutionary biology can be tackled from the top-down, the bottom-up, or from the middle-out. Given the emergent and contingent nature of this process, we have chosen to take the latter approach, both as a mechanistic link to developmental biology and as a rational means of identifying signaling mechanisms based on their functional genomic significance. Using this approach, we have been able to configure a working model for lung evolution by reverse-engineering lung surfactant from the mammalian lung to the swim bladder of fish. Based on this archetypal cell-molecular model, we have reduced evolutionary biology to cell communication, starting with unicellular organisms communicating with the environment, followed by cell-cell communication to generate metazoa, culminating in the communication of genetic information between generations, i.e. reproduction. This model predicts the evolution of physiologic systems-including development, homeostasis, disease, regeneration/repair, and aging- as a logical consequence of biology reducing entropy. This approach provides a novel and robust way of formulating refutable, testable hypotheses to determine the ultimate origins and first principles of physiology, providing candidate genes for phenotypes hypothesized to have mediated evolutionary changes in structure and/or function. Ultimately, it will form the basis for predictive medicine and molecular bioethics, rather than merely showing associations between genes and pathology, which is an unequivocal Just So Story. In this new age of genomics, our reach must exceed our grasp.
TGF-β1 and its target gene encoding plasminogen activator inhibitor-1 (PAI-1) are major regulators of capillary outgrowth, vessel maturation and angiogenic network stability. The increasing realization of the complexity of PAI-1 action in the vascular system requires analysis of specific signaling events that impact its expression in a physiologically-relevant cell system. PAI-1 was required for tubular differentiation and maintenance of cellular survival in complex gels since targeted disruption of PAI-1 synthesis or activity with antisense constructs or function-blocking antibodies resulted in network regression. Indeed, serum-deprivation-induced apoptosis of tubulogenic T2 cells was concentration-dependently inhibited by addition of a stable PAI-1 mutant protein consistent with the established pro-survival role of PAI-1 in vascular endothelial cells. PAI-1 induction and ERK pathway activation in response to TGF-β1 was attenuated by EGFR signaling blockade (with AG1478) or preincubation with the MMP/ADAM inhibitor GM6001. The combination of AG1478 + GM6001 completely ablated both responses suggesting that EGFR transactivation is important in PAI-1 gene control and may, at least partially, involve ligand shedding. TGF-β1-stimulated PAI-1 induction was preceded, in fact, by EGFR phosphorylation on Y845 (a src kinase target residue). EGFR1 knockdown with lentiviral shRNA constructs, moreover, effectively decreased (by >75%) TGF-β1-stimulated PAI-1 expression whereas infection with control (i.e. GFP) viruses had no effect. TGF-β1 failed to induce PAI-1 synthesis in EGFR-deficient fibroblasts while introduction of a wild-type EGFR1 construct in EGFR(-/-) cells rescued the PAI-1 response to TGF-β1 confirming, at a genetic level, the targeted knockdown data. The continued clarification of novel cooperative signaling cascades that impact expression of important angiogenic genes (e.g. PAI-1) may provide therapeutically useful targets to manage the pathophysiology of human neoplastic and vascular diseases.
