FEBS Letters最新文献

Almost all organisms on earth undergo rhythmic physiological and behavioral changes over the course of day. These rhythms are fundamental in most organisms and are referred to as circadian rhythms. The molecular mechanisms regulating these changes have evolved significantly in different kingdoms of life and they engage in crosstalk with most cellular functions. These molecular mechanisms have been studied for a long time using different model organisms and carefully designed experiments. In the past two decades or so, with advances in high throughput technologies and access to ever increasing computational power, the molecular mechanisms regulating circadian rhythms are being explored at multiple spatial and temporal scales. In this review, we introduce diverse regulatory mechanisms of circadian rhythms. We then focus on the proteins involved in circadian regulation, their structures, complexes and dynamics. This is followed by a review of computational methods such as structural modeling, integrative modeling and molecular simulations as applied to understanding the clock proteins in different organisms and insights obtained from the same. Finally, we highlight the limitations and future prospects of these methods in understanding the circadian regulation.

ETS family transcription factors can mediate mutant p53 functions, but there has been no comprehensive analysis of p53 interaction across the ETS family. By comparing direct mutant p53 binding between 26 ETS proteins, we found that all bound mutant p53, but relative binding differed significantly. The ETS DNA binding domain provided a common interaction interface, but strong binding required an alternate interaction domain highlighted by a PXXPP motif found in five ETS proteins. Genome-wide mapping found that the ETS protein ERG mediated some mutant p53 DNA binding in prostate cancer cells. Lastly, ETS proteins that interact strongly with mutant p53 tended to be upregulated in p53 mutant ovarian cancer. These results identify multiple ETS family members that could mediate mutant p53 function in cancer. Impact statement The mechanisms behind gain-of-function mutant p53 remain unclear. Here we identify distinct domains and a novel motif that can mediate binding of mutant p53 to multiple different ETS family transcription factors.

During gene expression, ribosome stalling frequently occurs and can lead to detrimental effects on cellular homeostasis. Several quality control mechanisms, including ribosome-associated quality control (RQC) and nonfunctional ribosomal RNA decay (NRD), have been identified to resolve these aberrant translation events. While the molecular mechanisms of each pathway have been extensively characterized, the mechanisms underlying the mutual regulation of the expression of pathway factors remain to be elucidated. Here, we employed a series of knockout mouse and human cell lines to investigate the crosstalk between translational quality control factors. Our findings revealed that the E3 ubiquitin ligase LTN1 suppresses expression of the E3 ubiquitin ligase RNF10 in a manner dependent on the RING domain of LTN1. This discovery offers new insights into the coordination of translational surveillance pathways.

EXPRESSION OF CONCERN: A. Li, X. Lin, X. Tan, B. Yin, W. Han, J. Zhao, J. Yuan, B. Qiang, and X. Peng, “ Circadian Gene Clock Contributes to Cell Proliferation and Migration of Glioma and Is Directly Regulated by Tumor-Suppressive miR-124,” FEBS Letters 587, no. 15 (2013): 2455-2460, https://doi.org/10.1016/j.febslet.2013.06.018.

This Expression of Concern is for the above article, published online on 19 June 2013, in Wiley Online Library (http://onlinelibrary.wiley.com/), and has been issued by agreement between the journal Editor-in-Chief, Michael Brunner; FEBS Press; and John Wiley and Sons Ltd. A third party reported that the siNC and siCLOCK images for U87MG cells in Figure 2D shared an overlapping section. An investigation by the journal confirmed these concerns.

The authors responded to an inquiry by the journal and supplied what were labeled as original data and a request for correction. The authors stated that the error in Figure 2D was caused by a mistake in the image compilation process. The journal reviewed the data provided, but they were unable to validate the experimental procedures used to generate the data. The journal reviewed the data provided, but were unable to confirm that it was acquired during the original study period. As such, the journal does not view a correction as appropriate. The Expression of Concern has been agreed to in order to inform and alert readers of the image overlap in Figure 2D. The authors disagree with the Expression of Concern.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a pivotal role in mounting an innate immune response against invading pathogens. Activation of this pathway by exogenous or endogenous stimuli triggers the downstream production of interferons and both pro-/anti-inflammatory cytokines. Over the past decade, hundreds of patents have been filed for the development and use of natural and synthetic STING agonists. For antivirals, synthetic STING agonists have been shown to be effective in both prophylactic and anaphylactic manners against viral infection and serve as vaccine adjuvants. This review summarizes the current application of STING agonists as antivirals to date against a variety of RNA and DNA viruses.

Phosphoinositides are transient signaling lipids, derived from the reversible phosphorylation of phosphatidylinositol on intracellular membranes, which serve as master regulators of many essential cellular functions. Seven distinct phosphoinositide species require precise spatiotemporal control, which is regulated by specific phosphatidylinositol kinases and phosphatases. Here, we review one such family, the inositol polyphosphate 5-phosphatases, which comprise 10 mammalian enzymes that dephosphorylate the 5-position phosphate group from the inositol head group of PtdIns(4,5)P₂, PtdIns(3,5)P₂, and/or PtdIns(3,4,5)P₃. Despite overlapping substrate specificities, the 5-phosphatases play nonredundant roles, including in development, as demonstrated by murine and zebrafish knockout studies. Mutations in several 5-phosphatase family members are associated with multisystem developmental and congenital syndromes. Associations between 5-phosphatase gene variants and diabetes and metabolic syndrome, neurodegenerative disease, and in rare cases cancer, are also emerging. Here, we provide a comprehensive discussion of the latest advances in this field, including updates on disease modeling and mechanisms.

Brain organoids, as self-organizing three-dimensional in vitro systems, offer a significant advantage over traditional models by enabling longitudinal analysis of developing human tissues. Their dynamic nature allows for the investigation of biological processes across time, a crucial 'fourth dimension' often lacking in highly reductionist in vitro models and essential to comprehensively study evolutionary and pathogenetic processes. Furthermore, the inherent genetic amenability of organoids facilitates the integration of advanced technologies, creating novel opportunities to exploit synthetic biology tools. In this regard, novel lineage tracing systems that integrate omics technologies are now dissecting complex human biological processes with unprecedented resolution. This review presents the current state of the art regarding the application of brain organoids for understanding human developmental processes related to cell lineage and temporal progression, highlighting studies that have developed dedicated lineage tracing tools. We further discuss the limitations inherent in current technologies and the potential improvements required to advance their fidelity, scalability, and translational relevance in modeling human brain development and disease.

Interleukin (IL) receptors play a pivotal role in immune regulation through coordinated interactions among multiple receptor subunits. Their cognate ligands, interleukins, orchestrate diverse immune responses by engaging distinct subunit combinations. Here, we developed a programmable IL-2 receptor surrogate ligand using a combinatorial bispecific agonist antibody strategy. By employing two complementary cell-based reporter systems that simultaneously monitor IL-2 receptor-mediated STAT5 activation and cell proliferation, we engineered a surrogate IL-2 receptor ligand that exhibits biased activation and differentiation of effector T and NK cells. This modular approach enables the development of tailored cytokine receptor surrogates with customized immunomodulatory functions.

Despite numerous studies, the biological and medical significance of inositol phosphates (InsPs) remains to be fully elucidated. One of the primary rate-limiting factors for InsP research is the difficulty in developing a method to specifically detect these molecules in complex biological matrices. Recent remarkable advancements in analytical chemistry such as nuclear magnetic resonance spectroscopy, mass spectrometry, and pertinent separation technologies have allowed the selective and sensitive differentiation of InsPs depending on the number and/or position of phosphate groups bound to the inositol ring. Thus, knowledge and experience of analytical chemistry have increasingly become a prerequisite for InsP studies. Establishing synthetic processes for functional InsPs and their analogs by organic chemists has also provided effective tools for quantitating their absolute abundances, as well as for investigating their molecular functions. This review briefly recapitulates the historical trajectory of the methodology applied to InsP research and highlights recently developed protocols using mass spectrometry coupled with liquid chromatography and capillary electrophoresis, in addition to a simple description of the chemical and chemoenzymatic synthesis of InsPs and their analogs.

Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint signaling and its blockade by checkpoint inhibitors are dependent on molecular interactions at the binding interface. In this work, the two complete complex structures in the protein native state of PD-1 with PD-L1, and the anti-PD-L1 antibody atezolizumab were investigated by atomic force microscopy (AFM) single-molecule force spectroscopy and predicted by AlphaFold modeling. AFM revealed that the PD-1/PD-L1 binding interface displayed greater stability than the atezolizumab/PD-L1 complex due to hydrogen bonding, while the hydrophobic effect enhanced binding flexibility at the atezolizumab/PD-L1 interface. The two complexes exhibited different bond lifetimes reflecting binding interface stability and transition distance related to the interface flexibility. This work provides relevant methodology to evaluate single-molecule macromolecular interactions. Impact statement Our research developed a novel and close-to-native physiological platform to evaluate protein interactions from structural, mechanical, and kinetic perspectives at the single-molecule level. This could be applied in the design of more effective checkpoint inhibitory molecules and provides relevant methodologies for evaluating single-molecule macromolecular interactions.