BACKGROUND: The postsynaptic density is an elaborate protein network beneath the postsynaptic membrane involved in the molecular processes underlying learning and memory. The postsynaptic density is built up from the same major proteins but its exact composition and organization differs between synapses. Mutations perturbing protein: protein interactions generally occurring in this network might lead to effects specific for cell types or processes, the understanding of which can be especially challenging.
RESULTS: In this work we use systems biology-based modeling of protein complex distributions in a simplified set of major postsynaptic proteins to investigate the effect of a hypomorphic Shank mutation perturbing a single well-defined interaction. We use data sets with widely variable abundances of the constituent proteins. Our results suggest that the effect of the mutation is heavily dependent on the overall availability of all the protein components of the whole network and no trivial correspondence between the expression level of the directly affected proteins and overall complex distribution can be observed.
CONCLUSIONS: Our results stress the importance of context-dependent interpretation of mutations. Even the weakening of a generally occurring protein: protein interaction might have well-defined effects, and these can not easily be predicted based only on the abundance of the proteins directly affected. Our results provide insight on how cell-specific effects can be exerted by a mutation perturbing a generally occurring interaction even when the wider interaction network is largely similar.

Sessile organisms, such as plants, developed various ways to sense and respond to external and internal stimuli to maximize their fitness through evolutionary time. Transcripts and protein regulation are, among many, the main mechanisms that plants use to respond to environmental changes. SKIP protein is one such, presenting an SNKW interacting domain, which is highly conserved among eukaryotes, where SKI interacting protein acts in regulating key processes. In the present work, many bioinformatics tools, such as phylogenetic relationships, gene structure, physical-chemical properties, conserved motifs, prediction of regulatory cis-elements, chromosomal localization, and protein-protein interaction network, were used to better understand the genome-wide SNW/SKIP domain-containing proteins. In total, 28 proteins containing the SNW/SKIP domain were identified in different plant species, including plants of agronomic interest. Two main protein clusters were formed in phylogenetic analysis, and gene structure analysis revealed that, in general, the coding region had no introns. Also, expression of these genes is possibly induced by abiotic stress stimuli. Primary structure analysis of the proteins revealed the existence of an evolutionarily conserved functional unit. But physicochemical properties show that proteins containing the SNW/SKIP domain are commonly unstable under in vivo conditions. In addition, the protein network, demonstrated that SKIP homologues could act by modulating plant fitness through gene expression regulation at the transcriptional and post-transcriptional levels. This could be corroborated by the expression number of gene copies of SKIP proteins in many species, highlighting it\'s crucial role in plant development and tolerance through the course of evolution.

Silencing of the fragile X messenger ribonucleoprotein 1 (FMR1) gene and a consequent lack of FMR protein (FMRP) synthesis are associated with fragile X syndrome, one of the most common inherited intellectual disabilities. FMRP is a multifunctional protein that is involved in many cellular functions in almost all subcellular compartments under both normal and cellular stress conditions in neuronal and non-neuronal cell types. This is achieved through its trafficking signals, nuclear localization signal (NLS), nuclear export signal (NES), and nucleolar localization signal (NoLS), as well as its RNA and protein binding domains, and it is modulated by various post-translational modifications such as phosphorylation, ubiquitination, sumoylation, and methylation. This review summarizes the recent advances in understanding the interaction networks of FMRP with a special focus on FMRP stress-related functions, including stress granule formation, mitochondrion and endoplasmic reticulum plasticity, ribosome biogenesis, cell cycle control, and DNA damage response.

Epigenetic control of gene expression is crucial for maintaining gene regulation. Sin3 is an evolutionarily conserved repressor protein complex mainly associated with histone deacetylase (HDAC) activity. A large number of proteins are part of Sin3/HDAC complexes, and the function of most of these members remains poorly understood. SAP25, a previously identified Sin3A associated protein of 25 kDa, has been proposed to participate in regulating gene expression programs involved in the immune response but the exact mechanism of this regulation is unclear. SAP25 is not expressed in HEK293 cells, which hence serve as a natural knockout system to decipher the molecular functions uniquely carried out by this Sin3/HDAC subunit. Using molecular, proteomic, protein engineering, and interaction network approaches, we show that SAP25 interacts with distinct enzymatic and regulatory protein complexes in addition to Sin3/HDAC. While the O-GlcNAc transferase (OGT) and the TET1 /TET2/TET3 methylcytosine dioxygenases have been previously linked to Sin3/HDAC, in HEK293 cells, these interactions were only observed in the affinity purification in which an exogenously expressed SAP25 was the bait. Additional proteins uniquely recovered from the Halo-SAP25 pull-downs included the SCF E3 ubiquitin ligase complex SKP1/FBXO3/CUL1 and the ubiquitin carboxyl-terminal hydrolase 11 (USP11), which have not been previously associated with Sin3/HDAC. Finally, we use mutational analysis to demonstrate that distinct regions of SAP25 participate in its interaction with USP11, OGT/TETs, and SCF(FBXO3).) These results suggest that SAP25 may function as an adaptor protein to coordinate the assembly of different enzymatic complexes to control Sin3/HDAC-mediated gene expression.

Nicotinamide mononucleotide (NMN) has emerged as a promising therapeutic intervention for age-related disorders, including type 2 diabetes. In this study, we confirmed the previously observed effects of NMN treatment on glucose uptake and investigated its underlying mechanisms in various tissues and cell lines. Through the most comprehensive proteomic analysis to date, we discovered a series of novel organ-specific effects responsible for glucose uptake as measured by the IPGTT: adipose tissue growing (suggested by increased protein synthesis and degradation and mTOR proliferation signaling upregulation). Notably, we observed the upregulation of thermogenic UCP1, promoting enhanced glucose conversion to heat in intermuscular adipose tissue while showing a surprising repressive effect on mitochondrial biogenesis in muscle and the brain. Additionally, liver and muscle cells displayed a unique response, characterized by spliceosome downregulation and concurrent upregulation of chaperones, proteasomes, and ribosomes, leading to mildly impaired and energy-inefficient protein synthesis machinery. Furthermore, our findings revealed remarkable metabolic rewiring in the brain. This involved increased production of ketone bodies, downregulation of mitochondrial OXPHOS and TCA cycle components, as well as the induction of well-known fasting-associated effects. Collectively, our data elucidate the multifaceted nature of NMN action, highlighting its organ-specific effects and their role in improving glucose uptake. These findings deepen our understanding of NMN\'s therapeutic potential and pave the way for novel strategies in managing metabolic disorders.

UNASSIGNED: Small cell lung cancer (SCLC) is a highly malignant and aggressive neuroendocrine tumor. With the rise of immunotherapy, it has provided a new direction for SCLC. However, due to the lack of prognostic biomarkers, the median overall survival of SCLC is still to be improved. This study aimed to explore novel biomarkers and tumor-infiltrating immune cell characteristics that may serve as potential diagnostic and prognostic markers in SCLC.
UNASSIGNED: Gene expression profiles from patients with SCLC were downloaded from the Gene Expression Omnibus (GEO) database, and tumor microenvironment (TME) infiltration profile data were obtained using CIBERSORT. The robust rank aggregation (RRA) method was utilized to integrate three SCLC microarray datasets downloaded from the GEO database and identify robust differentially expressed genes (DEGs) between normal and tumor tissue samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the functions of the robust DEGs. Subsequently, protein-protein interaction networks and key modules were constructed by Cytoscape, and hub genes were selected from the whole network using the plugin cytoHubba. Survival analysis of hub genes was performed by Kaplan-Meier plotter in 18 patients with extensive-stage SCLC.
UNASSIGNED: A total of 312 robust DEGs, including 55 upregulated and 257 downregulated genes, were screened from 129 SCLC tissue samples and 44 normal tissue samples. GO and KEGG enrichment analyses revealed that the robust DEGs were predominantly involved in human T-cell leukemia virus 1 infection, focal adhesion, complement and coagulation cascades, tumor necrosis factor (TNF) signaling pathway, and ECM-receptor interaction, which are closely associated with the development and progression of SCLC. Subsequently, three DEGs modules and six hub genes (ITGA10, DUSP12, PTGS2, FOS, TGFBR2, and ICAM1) were identified through screening with the Cytoscape plugins MCODE and cytoHubba, respectively. Immune cell infiltration analysis by the CIBERSORT algorithm revealed that resting memory CD4+ T cells were the predominant infiltrating immune cells in SCLC. In addition, Kaplan-Meier plotter revealed that the gene prostaglandin-endoperoxide synthase 2 (PTGS2) was a potential prognostic biomarker of SCLC.
UNASSIGNED: Hub genes and tumor-infiltrating immune cells may be the molecular mechanisms underlying the development of SCLC, and this finding could contribute to the formulation of individualized immunotherapy strategies for SCLC.

Alzheimer\'s disease has become a major public health issue. While extensive research has been conducted in the last few decades, few drugs have been approved by the FDA to treat Alzheimer\'s disease. There is still an urgent need for understanding the disease pathogenesis, as well as identifying new drug targets for further drug discovery. Alzheimer\'s disease is known to arise from a build-up of amyloid beta (Aβ) plaques as well as tangles of tau proteins. Along similar lines to Alzheimer\'s disease, inflammation in the brain is known to stem from the degeneration of tissue and build-up of insoluble materials. A minireview was conducted in this work assessing the genes, proteins, reactions, and pathways that link brain inflammation and Alzheimer\'s disease. Existing tools in Systems Biology were implemented to build protein interaction networks, mainly for the classical complement pathway and G protein-coupled receptors (GPCRs), to rank the protein targets according to their interactions. The top 10 protein targets were mainly from the classical complement pathway. With the consideration of existing clinical trials and crystal structures, proteins C5AR1 and GARBG1 were identified as the best targets for further drug discovery, through computational approaches like ligand-protein docking techniques.

This study was aimed at investigating the pathogenesis of chronic obstructive pulmonary disease (COPD) caused by smoking-based on bioinformatics analysis and in vitro experimental evidence. The GEO, GEO2R, TargetScan, miRDB, miRWalk, DAVID, and STRING databases were used for bioinformatics analysis. The mRNA expression and the protein levels were determined by real-time PCR and ELISA. After taking the intersection of the diversified results of the databases, four differentially expressed miRNAs (hsa-miR-146a, hsa-miR-708, hsa-miR-150, and hsa-miR-454) were screened out. Subsequently, a total of 57 target genes of the selected miRNAs were obtained. The results of DAVID analysis showed that the selected miRNAs participated in COPD pathogenesis through long-term potentiation, the TGF-β signaling pathway, the PI3K-Akt signaling pathway, etc. The results of STRING prediction showed that TP53, EP300, and MAPK1 were the key nodes of the PPI network. The results of the confirmatory experiment showed that, compared with the control group, the mRNA expression of ZEB1, MAPK1, EP300, and SP1 were up-regulated, while the expression of MYB was down-regulated and the protein levels of ZEB1, MAPK1, and EP300 were increased. Taken together, miRNAs (hsa-miR-146a, hsa-miR-708, hsa-miR-150, and hsa-miR-454) and their regulated target genes and downstream protein molecules (ZEB1, EP300, and MAPK1) may be closely related to the pathological process of COPD.

A fundamental principle of biology is that proteins tend to form complexes to play important roles in the core functions of cells. For a complete understanding of human cellular functions, it is crucial to have a comprehensive atlas of human protein complexes. Unfortunately, we still lack such a comprehensive atlas of experimentally validated protein complexes, which prevents us from gaining a complete understanding of the compositions and functions of human protein complexes, as well as the underlying biological mechanisms. To fill this gap, we built Human Protein Complexes Atlas (HPC-Atlas), as far as we know, the most accurate and comprehensive atlas of human protein complexes available to date. We integrated two latest protein interaction networks, and developed a novel computational method to identify nearly 9000 protein complexes, including many previously uncharacterized complexes. Compared with the existing methods, our method achieved outstanding performance on both testing and independent datasets. Furthermore, with HPC-Atlas we identified 751 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-affected human protein complexes, and 456 multifunctional proteins that contain many potential moonlighting proteins. These results suggest that HPC-Atlas can serve as not only a computing framework to effectively identify biologically meaningful protein complexes by integrating multiple protein data sources, but also a valuable resource for exploring new biological findings. The HPC-Atlas webserver is freely available at http://www.yulpan.top/HPC-Atlas.

The mammalian sirtuin family, consisting of SIRT1-SIRT7, plays a vital role in various biological processes, including cancer, diabetes, neurodegeneration, cardiovascular disease, cellular metabolism, and cellular homeostasis maintenance. Due to their involvement in these biological processes, modulating sirtuin activity seems promising to impact immune- and aging-related diseases, as well as cancer pathways. However, more understanding is required regarding the safety and efficacy of sirtuin-targeted therapies due to the complex regulatory mechanisms that govern their activity, particularly in the context of multiple targets. In this study, the interaction landscape of the sirtuin family was analyzed using a systems biology approach. A sirtuin protein-protein interaction network was built using the Cytoscape platform and analyzed using the NetworkAnalyzer and stringApp plugins. The result revealed the sirtuin family\'s association with numerous proteins that play diverse roles, suggesting a complex interplay between sirtuins and other proteins. Based on network topological and functional analysis, SIRT1 was identified as the most prominent among sirtuin family members, demonstrating that 25 of its protein partners are involved in cancer, 22 in innate immune response, and 29 in aging, with some being linked to a combination of two or more pathways. This study lays the foundation for the development of novel therapies that can target sirtuins with precision and efficacy. By illustrating the various interactions among the proteins in the sirtuin family, we have revealed the multifaceted roles of SIRT1 and provided a framework for their possible roles to be precisely understood, manipulated, and translated into therapeutics in the future.