A phosphatidylinositol 4,5-bisphosphate redistribution-based sensing mechanism initiates a phagocytosis programing

Abstract

Phagocytosis is one of the earliest cellular functions, developing approximately 2 billion years ago. Although FcR-based phagocytic signaling is well-studied, how it originated from ancient phagocytosis is unknown. Lipid redistribution upregulates a phagocytic program recapitulating FcR-based phagocytosis with complete dependence on Src family kinases, Syk, and phosphoinositide 3-kinases (PI3K). Here we show that in phagocytes, an atypical ITAM sequence in the ancient membrane anchor protein Moesin transduces signal without receptor activation. Plasma membrane deformation created by solid structure binding generates phosphatidylinositol 4,5-bisphosphate (PIP2) accumulation at the contact site, which binds the Moesin FERM domain and relocalizes Syk to the membrane via the ITAM motif. Phylogenic analysis traces this signaling using PI3K and Syk to 0.8 billion years ago, earlier than immune receptor signaling. The proposed general model of solid structure phagocytosis implies a preexisting lipid redistribution-based activation platform collecting intracellular signaling components for the emergence of immune receptors.

ERM Proteins at the Crossroad of Leukocyte Polarization, Migration and Intercellular Adhesion

“…However, considering that ERMs can also work as protein-associated modules to transmit signaling through the binding of the Src kinase Syk to the immunoreceptor tyrosine-based activation motif (ITAM) of their FERM domain [110], a provocative study has suggested that ERMs may stimulate phagocytosis through receptor-independent mechanisms. In this way, they would act as phylogenetically conserved mechanotransducers that activate PI3K in response to the deformations of the PM, which accumulate PIP 2 at the contact sites with foreign cells and particles, recruiting ERMs to the emerging phagocytic cup [111]. Nevertheless, while ERMs can regulate phagocytosis through a signaling pathway similar to that triggered by the ITAMs of FcγRs, the absence of moesin does not disturb internalization of IgG-coated particles, suggesting that ERMs are not essential for opsonization-mediated internalization.…”

“…Nevertheless, while ERMs can regulate phagocytosis through a signaling pathway similar to that triggered by the ITAMs of FcγRs, the absence of moesin does not disturb internalization of IgG-coated particles, suggesting that ERMs are not essential for opsonization-mediated internalization. On the contrary, ERMs seem to improve phagocytosis mediated by those mechanisms in which neither opsonization nor ITAM-bearing receptors are involved, such as the clearance of microorganisms and apoptotic cells by direct binding of scavenger receptors and receptors of phosphatidyl serine (PS), respectively [111]. Although attractive, the mechanotransduction model by which the PIP 2 -ERM-ITAM-Syk axis may collaborate with receptor-mediated opsonisation-independent phagocytosis leads to some unanswered questions.…”

C-reactive protein (CRP) recognizes uric acid crystals and recruits proteases C1 and MASP1

“…However, Clec12A is an inhibitory receptor that limits inflammatory responses, while potentiating type I interferon (IFN) responses [13][14][15] . Independent of recognition by receptors, MSU crystals activate immune cells by interacting with membrane cholesterol 16 or inducing membrane deformation 17 . Under physiological conditions, opsonization of the crystals with complement or other opsonins may also eliminate the need for specific crystal receptors.…”

A PI(4,5)P2‐derived “gasoline engine model” for the sustained B cell receptor activation

“…IP3 is a key regulator of the cytoplasmic Ca 2+ concentration by controlling a Ca 2+ channel IP3 receptor on the endoplasmic reticulum (ER) . In addition to being the precursor of DAG and IP3, PI(4,5)P2 is also a key messenger that regulates the polymerization of the actin cytoskeleton, plasma membrane tension, exocytosis, membrane fusion, activity of ion channels, and cell adhesion, etc . Thus, PI(4,5)P2 is of great importance during receptor signaling and cell activation.…”