CELL ACTIVATION BY LPS AND G-PROTEIN SIGNALLING

Corsi-Romanelli MM. Cell activation by LPS and G-protein signalling. International Journal of Infection. 2026;10(1):10-13.

M.M. Corsi-Romanelli^*

Department of Biomedical Sciences for Health, University of Milan, Italy.

*Correspondence to:
Massimiliano M. Corsi-Romanelli,
Department of Biomedical Sciences for Health,
University of Milan,
20133 Milan, Italy.
e-mail: mmcorsi@unimi.it

Received: 02 February, 2026 Accepted: 05 March, 2026

ISSN 3103-6678 [online] Copyright 2026 © by Biolife-publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

Guanine nucleotide-binding proteins (G-proteins) are proteins that send heterotrimeric molecular signals within cells following various stimuli. G-proteins act as cellular switches and are often associated with G-protein coupled receptors (GPCRs) that are activated when they bind guanosine triphosphate (GTP) and deactivated when GTP hydrolyzes to guanosine diphosphate (GDP). When lipopolysaccharide (LPS) binds to its cell surface receptor, the signal is transduced into the cell by G-proteins. Stimulation of the ligand to its receptor activates the G-protein and a cascade of internal signalling within the cell. At the site of infection, G-proteins trigger signals that lead to the production of inflammatory molecules such as cytokines. G-proteins also regulate blood vessel permeability, vasodilation, pain, and inflammation. Dysregulation of G-proteins can cause tumors, endocrine diseases, or neurological disorders. LPS is a highly inflammatory endotoxin found in the outer membrane of Gram-negative bacteria that activates TLR4 to cause immune cell activation. On macrophages, LPS is captured by LPS-binding protein (LBP), activates TLR4, and triggers a cascade of events that leads to the production of inflammatory cytokines and chemokines. LPS causes damage to the endothelium of blood vessels, resulting in edema, intravascular coagulation, capillary obstruction, and edema. LPS binds to the TLR4 receptor, not a GPCR, activating the innate immune response. LPS does not directly activate G-proteins, but indirectly modulates GPCRs and induces the production of nitric oxide (NO), which interferes with G-protein signalling and contributes to vasodilation and hypotension. In infections, G protein-mediated signaloling can be altered, and TLR4-activated pathways can interfere with the cellular response. In sepsis, LPS levels are increased, and G-protein dysfunction can occur, leading to vasodilation and septic shock. LPS activates TLR4 and triggers intracellular cascades of MyD88, TRIF, and NF-kB, resulting in the production of inflammatory mediators that alter the behavior of G-proteins and GPCRs.

KEYWORDS: Lipopolysaccharide, G-protein, LPS, cellular signalling, G-protein coupled receptor, immune

INTRODUCTION

Guanine nucleotide-binding proteins (G-proteins) are a family of proteins that send heterotrimeric a, b, and g molecular signals into cells following various external or internal stimuli (1). G-proteins are anchored to the cell’s internal membrane and activate cellular responses by exchanging guanosine diphosphate (GDP) to bind guanosine triphosphate (GTP) when the G-protein coupled receptor (GPCR) receives a ligand (2). G-proteins are often associated with GPCRs, which detect external signals. G proteins are molecular switches that are activated when they bind GTP and deactivated when GTP hydrolyzes to GDP. When a compound, such as lipopolysaccharide (LPS) or a drug, binds to a cell surface receptor, the signal is transduced within the cell by G-proteins, allowing the organism to respond to the stimulus (3). Thus, when a ligand binds to its cell surface receptor, the G-protein is activated and initiates a cascade of internal signalling within the cell that can lead to pathophysiological stimuli.

G-proteins are often associated with GPCRs, which detect external signals, including immune signals (4). During a bacterial or viral infection, G-proteins are involved in various processes, such as immune system activation (5). When a pathogen or a bacterial product like LPS enters the body, receptors on the surface of immune cells recognize the threat and activate G-proteins, triggering signals that lead to the production of inflammatory molecules like cytokines and the migration of immune cells to the site of infection (6). G-proteins regulate blood vessel permeability, vasodilation, pain, and inflammation (7). These effects work against infections, but if they are excessive, they can cause harmful adverse reactions in the body. Therefore, LPS serves as a danger signal for the human immune system. G-proteins are the target of many drugs because a large percentage of them act on GPCRs (8). Alterations in G-proteins can cause tumors, endocrine diseases, or neurological disorders.

LIPOPOLYSACCHARIDE

LPS, which is also known as endotoxin, is a key molecule in the outer membrane of Gram-negative bacteria (9). It protects the bacteria, but when released, it is a highly inflammatory compound capable of activating the host’s immune response, causing fever, inflammation, and, in severe cases, death. LPS is composed of three parts: Lipid A (responsible for toxicity/endotoxin), the oligosaccharide core, the O-antigen (polysaccharide side chain) (10). LPS is located exclusively in the outer membrane leaflet of Gram-negative bacteria, contributing to their structural stability. The primary effect of LPS on the immune system is the activation of the innate immune response. It acts as a powerful alarm signal indicating the presence of a bacterial infection (11).

Cells recognize LPS through highly specific receptor systems, such as Toll-like receptor 4 (TLR4), present on the surface of macrophages and dendritic cells. On the macrophage cell, LPS is captured by the LPS-binding protein (LBP) and presented to the complex formed by CD14 and MD-2, which then activates TLR4 (12). Activation of TLR4 triggers a cascade of events that leads to the production of inflammatory cytokines such as IL-1, TNF, IL-6, and IFNs, and chemokines such as IL-8, produced by neutrophils (13). LPS causes endothelial damage in blood vessels, as the vessels become more permeable and the vascular content spills over into the tissues, causing edema, as occurs in acute respiratory distress syndrome (ARDS) (14). Furthermore, disseminated intravascular coagulation occurs, with obstruction of the blood capillaries and hemorrhages (15). When LPS enters the peripheral circulation, it can trigger a “cytokine storm”, an uncontrolled immune response that is the pathophysiological basis of septic shock, a severe systemic reaction that leads to a drop in blood pressure and impaired coagulation (16). Cytokine storms result in an uncontrolled release of inflammatory mediators, causing organ damage and ultimately patient death (17).

LPS HAS AN INDIRECT EFFECT ON G-PROTEINS THROUGH IMMUNE RECEPTORS

LPS binds to the TLR4 receptor and not to a GPCR (18). This activates intracellular NF-κB pathways, which lead to the production of inflammatory cytokines such as TNF, IL-1, IL-6, and certain chemokines, that leads to the activation of the innate immune response (19). LPS does not directly activate G-proteins, but indirectly modulates GPCRs, as the released cytokines can influence them (20). In addition, LPS induces the production of nitric oxide (NO) (via iNOS), which interferes with G-protein signalling and contributes to vasodilation and hypotension (21).

In sepsis, G-protein-mediated signalling can be altered, and TLR4-activated pathways can interfere, altering the cellular response. In severe Gram-negative bacterial infections, where LPS levels are significantly increased, G-protein dysfunction can occur, especially in the cardiovascular system, an effect that contributes to vasodilation and septic shock (22). Therefore, LPS does not directly act on G-proteins, but alters their function indirectly through inflammation and immune signalling. G-proteins have different subunits: Gαs, Gαi, and Gαq (23). LPS-induced inflammation can reduce Gαs activity, resulting in lower cAMP production, increased inhibitory signals (Gαi), and a reduced cellular response (24). Disruption of certain balances leads cells to respond less favorably to physiological stimuli.

LPS increases the production of inflammatory cytokines that promote GPCR phosphorylation and receptor internalization, resulting in reduced sensitivity to ligands (25). Activation of TLR4 by LPS leads to intracellular MyD88, TRIF, and NF-kB cascades, resulting in the production of inflammatory mediators that alter the behavior of G proteins and GPCRs (26). MyD88 is a key adaptor protein in innate immunity receptor signalling that does not directly alter the behavior of G-proteins or GPCRs, two distinct signalling systems, but can indirectly cross-react (27). MyD88 is an important protein in TLR, and IL-1 receptor signalling and enhances the inflammatory response (26). When these receptors recognize a pathogen, MyD88 is recruited, activates kinases such as IRAK, leads to the activation of NF-κB, and causes the production of inflammatory cytokines (28).

CONCLUSIONS

In conclusion, LPS activates the immune system via TLR4, producing severe inflammation and indirectly altering G-proteins, making cells less responsive to normal signals. LPS activates MyD88, which does not directly modify G-proteins or GPCRs, but acts via inflammatory signals with the final effect of an indirect regulation of the GPCR-mediated response.

Conflict of interest

The author declares that they have no conflict of interest.

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