Sub-cellular biochemistry最新文献

The co-chaperone p50/Cdc37 is an important partner for Hsp90, assisting in molecular chaperone activities, particularly with regard to the regulation of protein kinases. Analysis of the structure of Hsp90-Cdc37-kinase complexes demonstrates the way in which Cdc37 interacts with and controls the folding of a large proportion of intracellular protein kinases. This co-chaperone thus stands at the hub of a multitude of intracellular signaling networks. Indeed, the influence of Cdc37 reaches beyond the housekeeping pathways of protein folding into the regulation of a wide range of cellular processes. This co-chaperone has attracted attention as a potential intermediate in carcinogenesis. Cdc37 is an attractive potential target in cancer due to (1) high expression in a number of tumor types and (2) control of multiple signaling pathways. These properties indicate (3) a potential for selectivity due to its elevated expression in malignant cells and (4) robustness, as the co-chaperone may control multiple growth signaling pathways and thus be less prone to evolution of resistance than less versatile oncoproteins. Cdc37 may also be involved in other aspects of pathophysiology and has been shown to be secreted in exosomes. Protein aggregation disorders have been linked to age-related declines in molecular chaperones and co-chaperones. Cdc37 also appears to be a potential agent in longevity due to its links to protein folding and autophagy, and it will be informative to study the role of Cdc37 maintenance/decline in aging organisms.

Cryo-electron tomography (cryo-ET) has emerged as a powerful tool in structural biology to study viruses and is undergoing a resolution revolution. Enveloped viruses comprise several RNA and DNA pleomorphic viruses that are pathogens of clinical importance to humans and animals. Considerable efforts in cryogenic correlative light and electron microscopy (cryo-CLEM), cryogenic focused ion beam milling (cryo-FIB), and integrative structural techniques are helping to identify virus structures within cells leading to a rise of in situ discoveries shedding light on how viruses interact with their hosts during different stages of infection. This chapter reviews recent advances in the application of cryo-ET in imaging enveloped viruses and the structural and mechanistic insights revealed studying the viral infection cycle within their eukaryotic cellular hosts, with particular attention to viral entry, replication, assembly, and egress during infection.

Posttranslational modifications (PTMs) regulate myriad cellular processes by modulating protein function and protein-protein interaction. Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone whose activity is responsible for the stabilization and maturation of more than 300 client proteins. Hsp90 is a substrate for numerous PTMs, which have diverse effects on Hsp90 function. Interestingly, many Hsp90 clients are enzymes that catalyze PTM, demonstrating one of the several modes of regulation of Hsp90 activity. Approximately 25 co-chaperone regulatory proteins of Hsp90 impact structural rearrangements, ATP hydrolysis, and client interaction, representing a second layer of influence on Hsp90 activity. A growing body of literature has also established that PTM of these co-chaperones fine-tune their activity toward Hsp90; however, many of the identified PTMs remain uncharacterized. Given the critical role of Hsp90 in supporting signaling in cancer, clinical evaluation of Hsp90 inhibitors is an area of great interest. Interestingly, differential PTM and co-chaperone interaction have been shown to impact Hsp90 binding to its inhibitors. Therefore, understanding these layers of Hsp90 regulation will provide a more complete understanding of the chaperone code, facilitating the development of new biomarkers and combination therapies.

During ageing molecular damage leads to the accumulation of several hallmarks of ageing including mitochondrial dysfunction, cellular senescence, genetic instability and chronic inflammation, which contribute to the development and progression of ageing-associated diseases including cardiovascular disease. Consequently, understanding how these hallmarks of biological ageing interact with the cardiovascular system and each other is fundamental to the pursuit of improving cardiovascular health globally. This review provides an overview of our current understanding of how candidate hallmarks contribute to cardiovascular diseases such as atherosclerosis, coronary artery disease and subsequent myocardial infarction, and age-related heart failure. Further, we consider the evidence that, even in the absence of chronological age, acute cellular stress leading to accelerated biological ageing expedites cardiovascular dysfunction and impacts on cardiovascular health. Finally, we consider the opportunities that modulating hallmarks of ageing offer for the development of novel cardiovascular therapeutics.

Ageing is associated with a morphological and functional decline of astrocytes with a prevalence of morphological atrophy and loss of function. In particular, ageing is manifested by the shrinkage of astrocytic processes: branches and leaflets, which decreases synaptic coverage. Astrocytic dystrophy affects multiple functions astrocytes play in the brain active milieu. In particular, and in combination with an age-dependent decline in the expression of glutamate transporters, astrocytic atrophy translates into deficient glutamate clearance and K⁺ buffering. Decreased astrocyte presence may contribute to age-dependent remodelling of brain extracellular space, hence affecting extrasynaptic signalling. Old astrocytes lose endfeet polarisation of AQP4 water channels, thus limiting the operation of the glymphatic system. In ageing, astrocytes down-regulate their antioxidant capacity leading to decreased neuroprotection. All these changes may contribute to an age-dependent cognitive decline.

Ageing is a complex process characterized by deteriorated performance at multiple levels, starting from cellular dysfunction to organ degeneration. Stem cell-based therapies aim to administrate stem cells that eventually migrate to the injured site to replenish the damaged tissue and recover tissue functionality. Stem cells can be easily obtained and cultured in vitro, and display several qualities such as self-renewal, differentiation, and immunomodulation that make them suitable candidates for stem cell-based therapies. Current animal studies and clinical trials are being performed to assess the safety and beneficial effects of stem cell engraftments for regenerative medicine in ageing and age-related diseases.Since alterations in cell-cell communication have been associated with the development of pathophysiological processes, new research is focusing on the modulation of the microenvironment. Recent research has highlighted the important role of some microenvironment components that modulate cell-cell communication, thus spreading signals from damaged ageing cells to neighbor healthy cells, thereby promoting systemic ageing. Extracellular vesicles (EVs) are small-rounded vesicles released by almost every cell type. EVs cargo includes several bioactive molecules, such as lipids, proteins, and genetic material. Once internalized by target cells, their specific cargo can induce epigenetic modifications and alter the fate of the recipient cells. Also, EV's content is dependent on the releasing cells, thus, EVs can be used as biomarkers for several diseases. Moreover, EVs have been proposed to be used as cell-free therapies that focus on their administration to slow or even reverse some hallmarks of physiological ageing. It is not surprising that EVs are also under study as next-generation therapies for age-related diseases.

In 1999, in a review by Beardsley, the potential of adult stem cells, in repair and regeneration was heralded (Beardsley Sci Am 281:30-31, 1999). Since then, the field of regenerative medicine has grown exponentially, with the capability of restoring or regenerating the function of damaged, diseased or aged human tissues being an underpinning motivation. If successful, stem cell therapies offer the potential to treat, for example degenerative diseases. In the subsequent 20 years, extensive progress has been made in the arena of adult stem cells (for a recent review see (Zakrzewski et al. Stem Cell Res Ther 10:68, 2019)). Prior to the growth of the adult stem cell research arena, much focus had been placed on the potential of embryonic stem cells (ESCs). The first research revealing the potential of these cells was published in 1981, when scientists reported the ability of cultured stem cells from murine embryos, to not only self-renew, but to also become all cells of the three germ layers of the developing embryo (Evans and Kaufman Nature 292:154-156, 1981), (Martin Proc Natl Acad Sci U S A 78:7634-7638, 1981). It took almost 20 years, following these discoveries, for this technology to translate to human ESCs, using donated human embryos. In 1998, Thomson et al. reported the creation of the first human embryonic cell line (Thomson et al. Science 282:1145-1147, 1998). However, research utilising human ESCs was hampered by ethical and religious constraints and indeed in 2001 George W. Bush restricted US research funding to human ESCs, which had already been banked. The contentious nature of this arena perhaps facilitated the use of and the research potential for adult stem cells. It is beyond the scope of this review to focus on ESCs, although their potential for enhancing our understanding of human development is huge (for a recent review see (Cyranoski Nature 555:428-430, 2018)). Rather, although ESCs and their epigenetic regulation will be introduced for background understanding, the focus will be on stem cells more generally, the role of epigenetics in stem cell fate, skeletal muscle, skeletal muscle stem cells, the impact of ageing on muscle wasting and the mechanisms underpinning loss, with a focus on epigenetic adaptation.

The proportion of elderly individuals is rising globally, and data have shown that as high as 8% of the elderly community suffer from malnutrition. Protein energy malnutrition has shown to elevate morbidity and mortality risk in the elderly; therefore, protein and energy supplement are needed for the elderly populations to create healthy conditions. This chapter describes about general structure of protein, protein turnover, amino acid metabolism including metabolism in the elderly, protein change in aging, supplementation of amino acid as well as vitamin and mineral for the elderly. The discussion in this section aims to provide a general description of protein, amino acids, changes in amino acid metabolism in the elderly, and the benefits of supplementing amino acids as well as vitamins and minerals for the elderly.

The Hsp90 chaperone is known to interact with a diverse array of client proteins. However, in every case examined, Hsp90 is also accompanied by a single or several co-chaperone proteins. One class of co-chaperone contains a tetratricopeptide repeat (TPR) domain that targets the co-chaperone to the C-terminal region of Hsp90. Within this class are Hsp90-binding peptidylprolyl isomerases, most of which belong to the FK506-binding protein (FKBP) family. Despite the common association of FKBP co-chaperones with Hsp90, it is abundantly clear that the client protein influences, and is often influenced by, the particular FKBP bound to Hsp90. Examples include Xap2 in aryl hydrocarbon receptor complexes and FKBP52 in steroid receptor complexes. In this chapter, we discuss the known functional roles played by FKBP co-chaperones and, where possible, relate distinctive functions to structural differences between FKBP members.

The immune system functions to protect the host from pathogens. To counter host defense mechanisms, pathogens have developed unique strategies to evade detection or restrict host immune responses. Programmed cell death is a major contributor to the multiple host responses that help to eliminate infected cells for obligate intracellular pathogens like viruses. Initiation of programmed cell death pathways during the early stages of viral infections is critical for organismal survival as it restricts the virus from replicating and serves to drive antiviral inflammation immune recruitment through the release of damage-associated molecular patterns (DAMPs) from the dying cell. Necroptosis has been implicated as a critical programmed cell death pathway in a diverse set of diseases and pathological conditions including acute viral infections. This cell death pathway occurs when certain host sensors are triggered leading to the downstream induction of mixed-lineage kinase domain-like protein (MLKL). MLKL induction leads to cytoplasmic membrane disruption and subsequent cellular destruction with the release of DAMPs. As the role of this cell death pathway in human disease becomes apparent, methods identifying necroptosis patterns and outcomes will need to be further developed. Here, we discuss advances in our understanding of how viruses counteract necroptosis, methods to quantify the pathway, its effects on viral pathogenesis, and its impact on cellular signaling.