SUMMARY
Heterotrimetic G proteins consist of four subfamilies (GS, Gi/O, Gq/11, and G12/13) that mediate signaling via G-protein-coupled receptors (GPCRs), principally by receptors binding Gα C termini. G-protein-coupling profiles govern GPCR-induced cellular responses, yet receptor sequence selectivity determinants remain elusive. Here, we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique Gα subunit C termini. For each receptor, we probed chimeric Gα subunit activation via a transforming growth factor-α (TGF-α) shedding response in HEK293 cells lacking endogenous Gq/11 and G12/13 proteins, and complemented G-protein-coupling profiles through a NanoBiT-G-protein dissociation assay. Interrogation of the dataset identified sequence-based coupling specificity features, inside and outside the transmembrane domain, which we used to develop a coupling predictor that outperforms previous methods. We used the predictor to engineer designer GPCRs selectively coupled to G12. This dataset of fine-tuned signaling mechanisms for diverse GPCRs is a valuable resource for research in GPCR signaling.
Highlights d Innovative bioinformatics pipeline reveals FAK as candidate synthetic lethal with Gaq d FAK is a central mediator of the GNAQ-driven oncogenic signaling circuitry d FAK activates YAP by MOB1 phosphorylation resulting in Hippo pathway inhibition d FAK represents a potential precision therapeutic target for uveal melanoma treatment
Invasion of a suitable host hepatocyte by mosquito-transmitted Plasmodium sporozoites is an essential early step in successful malaria parasite infection. Yet, precisely how sporozoites target their host cell and facilitate productive infection remains largely unknown. Here, we found that the hepatocyte EphA2 receptor was critical for establishing a permissive intracellular replication compartment, the parasitophorous vacuole. Sporozoites productively infected hepatocytes with high EphA2 expression and deletion of EphA2 protected mice from liver infection. Lack of host EphA2 phenocopied the lack of the sporozoite proteins P52 and P36. Our data suggests that P36 engages EphA2, which is likely to be a key step to establish the permissive replication compartment.
G protein‐coupled receptors (GPCRs) and heterotrimeric G proteins play central roles in a diverse array of cellular processes. As such, dysregulation of GPCRs and their coupled heterotrimeric G proteins can dramatically alter the signalling landscape and functional state of a cell. Consistent with their fundamental physiological functions, GPCRs and their effector heterotrimeric G proteins are implicated in some of the most prevalent human diseases, including a complex disease such as cancer that causes significant morbidity and mortality worldwide. GPCR/G protein‐mediated signalling impacts oncogenesis at multiple levels by regulating tumour angiogenesis, immune evasion, metastasis, and drug resistance. Here, we summarize the growing body of research on GPCRs and their effector heterotrimeric G proteins as drivers of cancer initiation and progression, and as emerging antitumoural therapeutic targets.
The facets of host control during Plasmodium liver infection remain largely unknown. We find that the SLC7a11-GPX4 pathway, which has been associated with the production of reactive oxygen species, lipid peroxidation, and a form of cell death called ferroptosis, plays a critical role in control of Plasmodium liver stage infection. Specifically, blocking GPX4 or SLC7a11 dramatically reduces Plasmodium liver stage parasite infection. In contrast, blocking negative regulators of this pathway, NOX1 and TFR1, leads to an increase in liver stage infection. We have shown previously that increased levels of P53 reduces Plasmodium LS burden in an apoptosis-independent manner. Here, we demonstrate that increased P53 is unable to control parasite burden during NOX1 or TFR1 knockdown, or in the presence of ROS scavenging or when lipid peroxidation is blocked. Additionally, SLC7a11 inhibitors Erastin and Sorafenib reduce infection. Thus, blocking the host SLC7a11-GPX4 pathway serves to selectively elevate lipid peroxides in infected cells, which localize within the parasite and lead to the elimination of liver stage parasites.
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