Membrane-induced Allosteric Control of Phospholipase C-β Isozymes

Charpentier, Thomas H.; Waldo, Gary L.; Barrett, Matthew O.; Huang, Wentao; Zhang, Qisheng; Harden, T. Kendall; Sondek, John

doi:10.1074/jbc.m114.586784

Cited by 34 publications

(57 citation statements)

References 52 publications

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“…It is well established that the heterotrimeric G protein Gα q -subunit activates PLCβ-lipase (42,43). Recent results indicate that membranes are essential for the activation of PLCβ isozymes by Gα q -subunit (44). Previously, Escribá et al showed that PE enhances the binding of Gα-subunit to model membranes (45).…”

Section: Discussionmentioning

confidence: 99%

Phospholipase Cβ1 induces membrane tubulation and is involved in caveolae formation

Inaba

Kishimoto

Murate

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Lipid membrane curvature plays important roles in various physiological phenomena. Curvature-regulated dynamic membrane remodeling is achieved by the interaction between lipids and proteins. So far, several membrane sensing/sculpting proteins, such as Bin/ amphiphysin/Rvs (BAR) proteins, are reported, but there remains the possibility of the existence of unidentified membrane-deforming proteins that have not been uncovered by sequence homology. To identify new lipid membrane deformation proteins, we applied liposome-based microscopic screening, using unbiased-darkfield microscopy. Using this method, we identified phospholipase Cβ1 (PLCβ1) as a new candidate. PLCβ1 is well characterized as an enzyme catalyzing the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP 2 ). In addition to lipase activity, our results indicate that PLCβ1 possessed the ability of membrane tubulation. Lipase domains and inositol phospholipids binding the pleckstrin homology (PH) domain of PLCβ1 were not involved, but the C-terminal sequence was responsible for this tubulation activity. Computational modeling revealed that the C terminus displays the structural homology to the BAR domains, which is well known as a membrane sensing/sculpting domain. Overexpression of PLCβ1 caused plasma membrane tubulation, whereas knockdown of the protein reduced the number of caveolae and induced the evagination of caveolin-rich membrane domains. Taken together, our results suggest a new function of PLCβ1: plasma membrane remodeling, and in particular, caveolae formation.phospholipase Cβ1 | membrane tubulation | microscopy screening | caveolae | BAR-like domain

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Section: Discussionmentioning

confidence: 99%

Phospholipase Cβ1 induces membrane tubulation and is involved in caveolae formation

Inaba

Kishimoto

Murate

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…These observations together suggest that the RhoGTPases may only regulate full-length plexin in the context of the cell membrane. Regulation of phospholipase C-beta by several elements has been proposed to rely on the membrane as the “conduit” of allostery (Charpentier et al, 2014). The membrane may play a similar role in plexin regulation by the RhoGTPases.…”

Section: Regulation Of Plexin By Rhogtpasesmentioning

confidence: 99%

Structural mechanisms of plexin signaling

Pascoe

Wang

Zhang

2015

Progress in Biophysics and Molecular Biology

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Signaling through plexin, the major cell surface receptor for semaphorin, plays critical roles in regulating processes such as neuronal axon guidance, angiogenesis and immune response. Plexin is normally kept inactive in the absence of semaphorin. Upon binding of semaphorin to the extracellular region, plexin is activated and transduces signal to the inside of the cell through its cytoplasmic region. The GTPase Activating Protein (GAP) domain in the plexin cytoplasmic region mediates the major intracellular signaling pathway. The substrate specificity and regulation mechanisms of the GAP domain have only been revealed recently. Many intracellular proteins serve as either upstream regulators or downstream transducers by directly interacting with plexin. The mechanisms of action for some of these proteins also start to emerge from recent studies. We review here these advances in the mechanistic understanding of plexin intracellular signaling from a structural perspective.

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“…In this regard, extracellular nucleotides act as inflammatory mediators and chemotactic agents via binding a variety of purinoceptors . Previous reports have demonstrated that in J774 macrophage, uridine 5′‐diphosphate (UDP) stimulates G‐protein coupled receptor P2Y 6 (G αq /G α11 subunits) to activate PLCβ3 thereby triggering PtdIns(4,5)P 2 hydrolysis . In this experiment, we again used time‐lapse video microscopy to monitor the plasmalemmal PtdIns(4,5)P 2 abundance in J774 macrophage in response to 10 μM UDP and the impact of 7KC.…”

Section: Resultsmentioning

confidence: 99%

7‐Ketocholesterol impairs phagocytosis and efferocytosis via dysregulation of phosphatidylinositol 4,5‐bisphosphate

Fairn

2018

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The plasma membrane is inhomogeneously organized containing both highly ordered and disordered nanodomains. 7-Ketocholesterol (7KC), an oxysterol formed from the nonenzymatic oxidation of cholesterol, is a potent disruptor of membrane order. Importantly, 7KC is a component of oxidized low-density lipoprotein and accumulates in macrophage and foam cells found in arterial plaques. Using a murine macrophage cell line, J774, we report that both IgG-mediated and phosphatidylserine-mediated phagocytic pathways are inhibited by the accumulation of 7KC. Examination of the well-studied Fcγ receptor pathway revealed that the cell surface receptor abundance and ligand binding are unaltered while downstream signaling and activation of spleen tyrosine kinase is not affected. However, while the recruitment of phospholipase Cγ1 was unaffected its apparent enzymatic activity was compromised resulting in sustained phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P ] levels and polymerized actin at the base of the phagocytic cup. Additionally, we found that 7KC prevented the activation of PLCβ downstream of the P2Y G-protein coupled receptor and that 7KC impaired PLCγ activity in response to a direct elevation of cytosolic calcium induced by ionomycin. Finally, we demonstrate that 7KC partly attenuates the activity of rapamycin recruitable constitutively active PLCβ3. Together, our results demonstrate that the accumulation of 7KC impairs macrophage function by altering PtdIns(4,5)P catabolism and, thus, impairing actin depolymerization required for the completion of phagocytosis.

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Membrane-induced Allosteric Control of Phospholipase C-β Isozymes

Cited by 34 publications

References 52 publications

Phospholipase Cβ1 induces membrane tubulation and is involved in caveolae formation

Phospholipase Cβ1 induces membrane tubulation and is involved in caveolae formation

Structural mechanisms of plexin signaling

7‐Ketocholesterol impairs phagocytosis and efferocytosis via dysregulation of phosphatidylinositol 4,5‐bisphosphate

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