The question of how genomic information is expressed to determine phenotypes is of central importance for basic and translational life science research and has been studied by transcriptomic and ...proteomic profiling. Here, we review the relationship between protein and mRNA levels under various scenarios, such as steady state, long-term state changes, and short-term adaptation, demonstrating the complexity of gene expression regulation, especially during dynamic transitions. The spatial and temporal variations of mRNAs, as well as the local availability of resources for protein biosynthesis, strongly influence the relationship between protein levels and their coding transcripts. We further discuss the buffering of mRNA fluctuations at the level of protein concentrations. We conclude that transcript levels by themselves are not sufficient to predict protein levels in many scenarios and to thus explain genotype-phenotype relationships and that high-quality data quantifying different levels of gene expression are indispensable for the complete understanding of biological processes.
Genomic information becomes translated into phenotypes via the complex and highly regulated process of gene expression and translation. Here, we review the relationship between mRNA and protein levels under various scenarios and conclude that transcript abundance by itself is not always sufficient to predict protein levels, emphasizing the complexity of the genotype-phenotype relationships.
We performed the first proteogenomic characterization of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) using paired tumor and adjacent liver tissues from 159 patients. Integrated ...proteogenomic analyses revealed consistency and discordance among multi-omics, activation status of key signaling pathways, and liver-specific metabolic reprogramming in HBV-related HCC. Proteomic profiling identified three subgroups associated with clinical and molecular attributes including patient survival, tumor thrombus, genetic profile, and the liver-specific proteome. These proteomic subgroups have distinct features in metabolic reprogramming, microenvironment dysregulation, cell proliferation, and potential therapeutics. Two prognostic biomarkers, PYCR2 and ADH1A, related to proteomic subgrouping and involved in HCC metabolic reprogramming, were identified. CTNNB1 and TP53 mutation-associated signaling and metabolic profiles were revealed, among which mutated CTNNB1-associated ALDOA phosphorylation was validated to promote glycolysis and cell proliferation. Our study provides a valuable resource that significantly expands the knowledge of HBV-related HCC and may eventually benefit clinical practice.
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•Proteomic subgroups stratify patient survival and allocate specific treatments•Alterations of the liver-specific proteome and metabolism in HCC are identified•Multi-omics profile of key signaling and metabolic pathways in HCC is depicted•CTNNB1 mutation-associated ALDOA phosphorylation promotes HCC cell proliferation
Proteogenomic characterization of HBV-related hepatocellular carcinoma (HCC) using paired tumor and adjacent liver tissues identifies three subgroups with distinct features in metabolic reprogramming, microenvironment dysregulation, cell proliferation, and potential therapeutics.
The development of low cost noble metal nanocatalysts with high activity and selectivity, high catalytic performance, convenient separation, and reusability is a significant challenge. Herein, the ...magnetic porous carbon (MPC) composite synthesized from metal organic framework (MOF) was used as a catalyst support to fabricate gold (Au) and palladium (Pd) nanoparticle (NP) based nanocatalysts. The MPC not only provided a large surface area and mesopores on which the active centers (Au and Pd NPs) were finely dispersed, but also exhibited superparamagnetic behaviour that enabled the magnetic separation and convenient recovery of the nanocatalysts from the reaction mixture. Thus, the nanocatalysts were repeatedly used without loss of catalytic efficiency. Both the Au/MPC and Pd/MPC nanocatalysts showed excellent catalytic activity for the reduction of 4-nitrophenol. Moreover, the Pd/MPC nanocatalyst exhibited higher efficiency toward hydrodechlorination of 4-chlorophenol compared to the other reported catalysts. This study indicated that the noble metal NPs (NMNPs) supported on MOF-derived MPC materials could act as promising catalysts exhibiting potential applications in numerous NMNP based catalytic reactions.
In medicine, there is an urgent need for protein biomarkers in a range of applications that includes diagnostics, disease stratification, and therapeutic decisions. One of the main technologies to ...address this need is MS, used for protein biomarker discovery and, increasingly, also for protein biomarker validation. Currently, data‐dependent analysis (also referred to as shotgun proteomics) and targeted MS, exemplified by SRM, are the most frequently used mass spectrometric methods. Recently developed data‐independent acquisition techniques combine the strength of shotgun and targeted proteomics, while avoiding some of the limitations of the respective methods. They provide high‐throughput, accurate quantification, and reproducible measurements within a single experimental setup. Here, we describe and review data‐independent acquisition strategies and their recent use in clinically oriented studies. In addition, we also provide a detailed guide for the implementation of SWATH‐MS (where SWATH is sequential window acquisition of all theoretical mass spectra)—one of the data‐independent strategies that have gained wide application of late.
Quantitative proteomics employing mass spectrometry is an indispensable tool in life science research. Targeted proteomics has emerged as a powerful approach for reproducible quantification but is ...limited in the number of proteins quantified. SWATH-mass spectrometry consists of data-independent acquisition and a targeted data analysis strategy that aims to maintain the favorable quantitative characteristics (accuracy, sensitivity, and selectivity) of targeted proteomics at large scale. While previous SWATH-mass spectrometry studies have shown high intra-lab reproducibility, this has not been evaluated between labs. In this multi-laboratory evaluation study including 11 sites worldwide, we demonstrate that using SWATH-mass spectrometry data acquisition we can consistently detect and reproducibly quantify >4000 proteins from HEK293 cells. Using synthetic peptide dilution series, we show that the sensitivity, dynamic range and reproducibility established with SWATH-mass spectrometry are uniformly achieved. This study demonstrates that the acquisition of reproducible quantitative proteomics data by multiple labs is achievable, and broadly serves to increase confidence in SWATH-mass spectrometry data acquisition as a reproducible method for large-scale protein quantification.SWATH-mass spectrometry consists of a data-independent acquisition and a targeted data analysis strategy that aims to maintain the favorable quantitative characteristics on the scale of thousands of proteins. Here, using data generated by eleven groups worldwide, the authors show that SWATH-MS is capable of generating highly reproducible data across different laboratories.
Mutations truncating a single copy of the tumor suppressor, BRCA2, cause cancer susceptibility. In cells bearing such heterozygous mutations, we find that a cellular metabolite and ubiquitous ...environmental toxin, formaldehyde, stalls and destabilizes DNA replication forks, engendering structural chromosomal aberrations. Formaldehyde selectively depletes BRCA2 via proteasomal degradation, a mechanism of toxicity that affects very few additional cellular proteins. Heterozygous BRCA2 truncations, by lowering pre-existing BRCA2 expression, sensitize to BRCA2 haploinsufficiency induced by transient exposure to natural concentrations of formaldehyde. Acetaldehyde, an alcohol catabolite detoxified by ALDH2, precipitates similar effects. Ribonuclease H1 ameliorates replication fork instability and chromosomal aberrations provoked by aldehyde-induced BRCA2 haploinsufficiency, suggesting that BRCA2 inactivation triggers spontaneous mutagenesis during DNA replication via aberrant RNA-DNA hybrids (R-loops). These findings suggest a model wherein carcinogenesis in BRCA2 mutation carriers can be incited by compounds found pervasively in the environment and generated endogenously in certain tissues with implications for public health.
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•Pervasive natural aldehydes selectively deplete BRCA2 and a few additional proteins•Inherited BRCA2 mutations sensitize to aldehyde-induced BRCA2 haploinsufficiency•BRCA2 haploinsufficiency causes genomic instability via unscheduled R-loops•Cellular or environmental aldehydes may incite cancer in BRCA2 mutation carriers
Environmental and endogenous aldehydes contribute to genome instability and potentially tumorigenesis through selective degradation of BRCA2.
This paper is mainly concerned with the existence of mild solutions and exact controllability for a class of fractional semilinear system of order q∈1,2 with instantaneous and noninstantaneous ...impulses. First, combining the Kuratowski measure of noncompactness and the Mönch fixed point theorem, we investigated the existence result for the considered system. It is remarkable that our assumptions for impulses and the nonlinear term are weaker than the Lipschitz conditions. Next, on this basis, the exact controllability for the considered system is determined. In the end, an example is provided to support the main findings.
The relative contribution of transcriptional and translational regulation in gene expression control has been intensely debated and remains a challenging question. Recent reports have suggested that ...protein abundance in mammalian cells is primarily controlled at the transcript‐level. In their recent work, Cheng et al () determined the proteomic and transcriptomic changes in cells responding to endoplasmic reticulum (ER) stress. Their analyses indicate that the ER stress response is significantly controlled at both the transcript and protein levels.
The relative contribution of transcriptional and translational regulation in gene expression control remains an open question. Vogel and colleagues (Cheng et al, ) show that the endoplasmic reticulum stress response is controlled at both the transcript and protein levels.
The inflammasomes are multiprotein complexes sensing tissue damage and infectious agents to initiate innate immune responses. Different inflammasomes containing distinct sensor molecules exist. The ...NLRP3 inflammasome is unique as it detects a variety of danger signals. It has been reported that NLRP3 is recruited to mitochondria-associated endoplasmic reticulum membranes (MAMs) and is activated by MAM-derived effectors. Here, we show that in response to inflammasome activators, MAMs localize adjacent to Golgi membranes. Diacylglycerol (DAG) at the Golgi rapidly increases, recruiting protein kinase D (PKD), a key effector of DAG. Upon PKD inactivation, self-oligomerized NLRP3 is retained at MAMs adjacent to Golgi, blocking assembly of the active inflammasome. Importantly, phosphorylation of NLRP3 by PKD at the Golgi is sufficient to release NLRP3 from MAMs, resulting in assembly of the active inflammasome. Moreover, PKD inhibition prevents inflammasome autoactivation in peripheral blood mononuclear cells from patients carrying NLRP3 mutations. Hence, Golgi-mediated PKD signaling is required and sufficient for NLRP3 inflammasome activation.
In budding yeast, the mitotic exit network (MEN), a GTPase signaling cascade, integrates spatial and temporal cues to promote exit from mitosis. This signal integration requires transmission of a ...signal generated on the cytoplasmic face of spindle pole bodies (SPBs; yeast equivalent of centrosomes) to the nucleolus, where the MEN effector protein Cdc14 resides. Here, we show that the MEN activating signal at SPBs is relayed to Cdc14 in the nucleolus through the dynamic localization of its terminal kinase complex Dbf2-Mob1. Cdc15, the protein kinase that activates Dbf2-Mob1 at SPBs, also regulates its nuclear access. Once in the nucleus, priming phosphorylation of Cfi1/Net1, the nucleolar anchor of Cdc14, by the Polo-like kinase Cdc5 targets Dbf2-Mob1 to the nucleolus. Nucleolar Dbf2-Mob1 then phosphorylates Cfi1/Net1 and Cdc14, activating Cdc14. The kinase-primed transmission of the MEN signal from the cytoplasm to the nucleolus exemplifies how signaling cascades can bridge distant inputs and responses.
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