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Conversations that count: Cellular interactions that drive T cell fate

2021-02-14T00:00

The relationship between the extrinsic environment and the internal transcriptional network is circular. Naive T cells first engage with antigen‐presenting cells to set transcriptional differentiation networks in motion. In turn, this regulates specific chemokine receptors that direct migration into distinct lymph node niches. Movement into these regions brings newly activated T cells into contact with accessory cells and cytokines that reinforce the differentiation programming to specify T cell function. We and others have observed similarities in the transcriptional networks that specify both CD4+ T follicular helper (T_FH) cells and CD8+ central memory stem‐like (T_SCM) cells. Here, we compare and contrast the current knowledge for these shared differentiation programs, compared to their effector counterparts, CD4+ T‐helper 1 (T_H1) and CD8+ short‐lived effector (T_SLEC) cells. Understanding the interplay between cellular interactions and transcriptional programming is essential to harness T cell differentiation that is fit for purpose; to stimulate potent T cell effector function for the elimination of chronic infection and cancer; or to amplify the formation of humoral immunity and longevity of cellular memory to prevent infectious diseases.

The diverse functionality of NQO1 and its roles in redox control

2021-03-20T00:00

In this review, we summarize the multiple functions of NQO1, its established roles in redox processes and potential roles in redox control that are currently emerging. NQO1 has attracted interest due to its roles in cell defense and marked inducibility during cellular stress. Exogenous substrates for NQO1 include many xenobiotic quinones. Since NQO1 is highly expressed in many solid tumors, including via upregulation of Nrf2, the design of compounds activated by NQO1 and NQO1-targeted drug delivery have been active areas of research. Endogenous substrates have also been proposed and of relevance to redox stress are ubiquinone and vitamin E quinone, components of the plasma membrane redox system. Established roles for NQO1 include a superoxide reductase activity, NAD⁺ generation, interaction with proteins and their stabilization against proteasomal degradation, binding and regulation of mRNA translation and binding to microtubules including the mitotic spindles. We also summarize potential roles for NQO1 in regulation of glucose and insulin metabolism with relevance to diabetes and the metabolic syndrome, in Alzheimer's disease and in aging. The conformation and molecular interactions of NQO1 can be modulated by changes in the pyridine nucleotide redox balance suggesting that NQO1 may function as a redox-dependent molecular switch.

Regulatory B cells: TIM‐1, transplant tolerance, and rejection

2021-01-22T00:00

Regulatory B cells (Bregs) ameliorate autoimmune disease and prevent allograft rejection. Conversely, they hinder effective clearance of pathogens and malignancies. Breg activity is mainly attributed to IL‐10 expression, but also utilizes additional regulatory mechanisms such as TGF‐β, FasL, IL‐35, and TIGIT. Although Bregs are present in various subsets defined by phenotypic markers (including canonical B cell subsets), our understanding of Bregs has been limited by the lack of a broadly inclusive and specific phenotypic or transcriptional marker. TIM‐1, a broad marker for Bregs first identified in transplant models, plays a major role in Breg maintenance and induction. Here, we expand on the role of TIM‐1⁺ Bregs in immune tolerance and propose TIM‐1 as a unifying marker for Bregs that utilize various inhibitory mechanisms in addition to IL‐10. Further, this review provides an in‐depth assessment of our understanding of Bregs in transplantation as elucidated in murine models and clinical studies. These studies highlight the major contribution of Bregs in preventing allograft rejection, and their ability to serve as highly predictive biomarkers for clinical transplant outcomes.

Interactions of zinc- and redox-signaling pathways

2021-02-24T00:00

Zinc and cellular oxidants such as reactive oxygen species (ROS) each participate in a multitude of physiological functions. There is considerable overlap between the affected events, including signal transduction. While there is no obvious direct connection between zinc and ROS, mainly because the bivalent cation zinc does not change its oxidation state in biological systems, these are linked by their interaction with sulfur, forming the remarkable triad of zinc, ROS, and protein thiols. First, zinc binds to reduced thiols and can be released upon oxidation. Thereby, redox signals are translated into changes in the free zinc concentration, which can act as zinc signals. Second, zinc affects oxidation of thiols in several ways, directly as well as indirectly. A protein incorporating many of these interactions is metallothionein (MT), which is rich in cysteine and capable of binding up to seven zinc ions in its fully reduced state. Zinc binding is diminished after (partial) oxidation, while thiols show increased reactivity in the absence of bound metal ions. Adding still more complexity, the MT promoter is controlled by zinc (via metal regulatory transcription factor 1 (MTF-1)) as well as redox (via nuclear factor erythroid 2-related factor 2 (NRF2)). Many signaling cascades that are important for cell proliferation or apoptosis contain protein thiols, acting as centers for crosstalk between zinc- and redox-signaling. A prominent example for shared molecular targets for zinc and ROS are active site cysteine thiols in protein tyrosine phosphatases (PTP), their activity being downregulated by oxidation as well as zinc binding. Because zinc binding also protects PTP thiols form irreversible oxidation, there is a multi-faceted reciprocal interaction, illustrating that zinc- and redox-signaling are intricately linked on multiple levels.

Modulation of the ubiquitin-proteasome system by marine natural products

2021-02-17T00:00

The ubiquitin-proteasome system (UPS) is a key player in the maintenance of cellular protein homeostasis (proteostasis). Since proteasome function declines upon aging leading to the acceleration of its progression and the manifestation of age-related pathologies, many attempts have been performed towards proteasome activation as a strategy to promote healthspan and longevity. The marine environment hosts a plethora of organisms that produce a vast array of primary and secondary metabolites, the majority of which are unique, exhibiting a wide spectrum of biological activities. The fact that these biologically important compounds are also present in edible marine organisms has sparked the interest for elucidating their potential health-related applications. In this review, we focus on the antioxidant, anti-aging, anti-aggregation and anti-photoaging properties of various marine constituents. We further discuss representatives of marine compounds classes with regard to their potential (direct or indirect) action on UPS components that could serve as UPS modulators and exert beneficial effects on conditions such as oxidative stress, aging and age-related diseases.

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Proteasome has been implicated in oxidative stress, aging and age-related diseases.

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Various marine natural products exert strong antioxidant activities.

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Various marine natural products possess anti-aging and anti-aggregation properties.

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Various marine natural products can serve as potential proteasome modulators.

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Various marine natural products represent promising anti-photoaging agents.

Oxidative eustress: On constant alert for redox homeostasis

2021-01-20T00:00

In the open metabolic system, redox-related signaling requires continuous monitoring and fine-tuning of the steady-state redox set point. The ongoing oxidative metabolism is a persistent challenge, denoted as oxidative eustress, which operates within a physiological range that has been called the ‘Homeodynamic Space’, the ‘Goldilocks Zone’ or the ‘Golden Mean’. Spatiotemporal control of redox signaling is achieved by compartmentalized generation and removal of oxidants. The cellular landscape of H₂O₂, the major redox signaling molecule, is characterized by orders-of-magnitude concentration differences between organelles. This concentration pattern is mirrored by the pattern of oxidatively modified proteins, exemplified by S-glutathionylated proteins. The review presents the conceptual background for short-term (non-transcriptional) and longer-term (transcriptional/translational) homeostatic mechanisms of stress and stress responses. The redox set point is a variable moving target value, modulated by circadian rhythm and by external influence, summarily denoted as exposome, which includes nutrition and lifestyle factors. Emerging fields of cell-specific and tissue-specific redox regulation in physiological settings are briefly presented, including new insight into the role of oxidative eustress in embryonal development and lifespan, skeletal muscle and exercise, sleep-wake rhythm, and the function of the nervous system with aspects leading to psychobiology.