G-protein coupled receptors (GPCRs) mediate crucial physiological functions in humans, have been implicated in an array of diseases, and are therefore prime drug targets. GPCRs signal via a multitude of pathways, mainly through G-proteins and β-arrestins, to regulate effectors responsible for cellular responses. The limited number of transducers results in different GPCRs exerting control on the same pathway, while the availability of signaling proteins in a cell defines the result of GPCR activation. The aim of this study was to construct the extended human GPCR network (hGPCRnet) and examine the effect that cell-type specificity has on GPCR signaling pathways. To achieve this, protein−protein interaction data between GPCRs, G-protein coupled receptor kinases (GRKs), Gα subunits, β-arrestins, and effectors were combined with protein expression data in cell types. This resulted in the hGPCRnet, a very large interconnected network, and similar cell-type-specific networks in which, distinct GPCR signaling pathways were formed. Finally, a user friendly web application, hGPCRnet (http://bioinformatics.biol. uoa.gr/hGPCRnet), was created to allow for the visualization and exploration of these networks and of GPCR signaling pathways. This work, and the resulting application, can be useful in further studies of GPCR function and pharmacology.

Alzheimer disease (AD) is a neurodegenerative disorder with an –as of yet– unclear etiology and pathogenesis. Research to unveil disease processes underlying AD often relies on the use of neurodegenerative disease model organisms, such as Caenorhabditis elegans. This study sought to identify biological pathways implicated in AD that are conserved in Homo sapiens and C. elegans. Protein–protein interaction networks were assembled for amyloid precursor protein (APP) and Tau in H. sapiens—two proteins whose aggregation is a hallmark in AD—and their orthologs APL-1 and PTL-1 for C. elegans. Global network alignment was used to compare these networks and determine similar, likely conserved, network regions. This comparison revealed that two prominent pathways, the APP-processing and the Tau-phosphorylation pathways, are highly conserved in both organisms. While the majority of interactions between proteins in those pathways are known to be associated with AD in human, they remain unexamined in C. elegans, signifying the need for their further investigation. In this work, we have highlighted conserved interactions related to AD in humans and have identified specific proteins that can act as targets for experimental studies in C. elegans, aiming to uncover the underlying mechanisms of AD.

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The nuclear envelope (NE) is a double-membrane system surrounding the nucleus of eukaryotic cells. A large number of proteins are localized in the NE, performing a wide variety of functions, from the bidirectional exchange of molecules between the cytoplasm and the nucleus to chromatin tethering, genome organization, regulation of signaling cascades, and many others. Despite its importance, several aspects of the NE, including its protein–protein interactions, remain understudied. In this work, we present NucEnvDB, a publicly available database of NE proteins and their interactions. Each database entry contains useful annotation including a description of its position in the NE, its interactions with other proteins, and cross-references to major biological repositories. In addition, the database provides users with a number of visualization and analysis tools, including the ability to construct and visualize protein–protein interaction networks and perform functional enrichment analysis for clusters of NE proteins and their interaction partners. The capabilities of NucEnvDB and its analysis tools are showcased by two informative case studies, exploring protein–protein interactions in Hutchinson–Gilford progeria and during SARS-CoV-2 infection at the level of the nuclear envelope.