Mutations in Phosphoinositide Metabolizing Enzymes and Human Disease

McCrea, Heather J.; Camilli, Pietro De

doi:10.1152/physiol.00035.2008

Cited by 163 publications

(204 citation statements)

References 110 publications

(160 reference statements)

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“…PKC are activated by the phospholipase C (PLC)-g enzymes, which are enriched in leukocytes and mediate conversion of phosphoinositide (4,5) bisphosphate (PIP 2 ) into inositol (1,4,5) trisphosphate (IP 3) and diacylglycerol. Consequently, the generation of IP 3 leads to intracellular Ca 21 release from the endoplasmic reticulum, which along with diacylglycerol production leads to the activation of cPKC [26][27][28].…”

Section: Discussionmentioning

confidence: 99%

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

et al. 2010

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Conventional PKC (cPKC)-a regulates TRIF-dependent IFN response factor 3 (IRF3)-mediated gene transcription, but its role in MyD88-dependent TLR signaling remains unknown. Herein, we demonstrate that PKC-a is induced by several MyD88-dependent TLR/IL-1R ligands and regulates cytokine expression in human and murine DC. First, inhibition of cPKC activity in human DC by cPKC-specific inhibitors, Gö 6976 or HBDDe, downregulated the production of classical inflammatory/immunomodulatory cytokines induced by TLR2, TLR5 or IL-1R but not by TLR3 stimulation. Similarly, dominant negative PKC-a repressed Pam 3 CSK 4 induced NF-jB-and AP-1-driven promoter activities in TLR2-expressing human embryonic kidney 293 T cells. Dominant negative PKC-a inhibited NF-jB reporter activity mediated by overexpression of MyD88 but not TRIF. Unexpectedly, BM-derived DC from PKC-a À/À mice exhibited decreased TNF-a and IL-12p40 production induced by both MyD88-and TRIF-dependent ligands. Furthermore, PKC-a is coupled to TLR2 signaling proximal to MyD88 since MAPK and IjB kinase-a/b phosphorylations and IjBa degradation were inhibited in PKC-a À/À BM-derived DC. Finally, co-immunoprecipitation assays revealed that PKC-a physically interacts with Pam 3 CSK 4 activated TLR2 in WT but not in MyD88 À/À DC. Collectively this study identifies a species-specific role of PKC-a as a key component that controls MyD88-dependent cytokine gene expression in human and mouse but differentially regulates production of TRIF-dependent cytokines.Key words: MyD88 . PKC . TLR Supporting Information available online Introduction TLR are a family of evolutionary conserved transmembrane proteins that are expressed on numerous cell types including Mf and DC. They function as pathogen recognition receptors, sensing a wide range of invading pathogens including bacteria, fungi and viruses through recognition of PAMP. Engagement of TLR by microbial products triggers the activation of two distinct signaling pathways: the MyD88-dependent and -independent pathways, Ã These authors contributed equally to this work.ÃÃ These authors contributed equally to this work. [4,5]. Recent studies identified several PKC isoforms as key regulators of TLR signaling pathways. PKC serine/threonine kinase family is classified into three groups according to their structure homology and co-factor regulation (conventional PKC (a, bI, bII, and g), novel PKC (d, e, y and Z/L) and atypical PKC (l/i and z)) [6,7]. PKC-e À/À Mf display a major defect in their ability to generate inflammatory mediators in response to LPS and are highly susceptible to Gram-positive and Gram-negative infections [8,9]. PKC-e is also involved in LPS-induced MAPK phosphatase 1 expression in MF and plays a critical role in LPS-induced IL-12p70 and TNF-a production in DC [10,11]. PKC-e À/À and PKC-d À/À MF display an impaired activation of NF-kB and MAPK downstream of TLR2 and TLR4 [8,12]. PKC-d is necessary to induce Stat-1 activation in response to LPS in murine MF [13]. PKC-z is implicated in LPS-induced MAPK and NF-kB...

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Section: Discussionmentioning

confidence: 99%

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

et al. 2010

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“…Examples of protein interactions with different PIs are provided. (Panel based in part on data from DiPaolo and Di Camilli 2006;McCrea and De Camilli 2009;and Kutateladze 2010. ) transcription.…”

Section: Small Gtpases and Phosphoinositidesmentioning

confidence: 99%

Phosphoinositides in Cell Architecture

Shewan

Eastburn²,

Mostov

2011

Cold Spring Harbor Perspectives in Biology

173

159

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Inositol phospholipids have been implicated in almost all aspects of cellular physiology including spatiotemporal regulation of cellular signaling, acquisition of cellular polarity, specification of membrane identity, cytoskeletal dynamics, and regulation of cellular adhesion, motility, and cytokinesis. In this review, we examine the critical role phosphoinositides play in these processes to execute the establishment and maintenance of cellular architecture. Epithelial tissues perform essential barrier and transport functions in almost all major organs. Key to their development and function is the establishment of epithelial cell polarity. We place a special emphasis on highlighting recent studies demonstrating phosphoinositide regulation of epithelial cell polarity and how individual cells use phosphoinositides to further organize into epithelial tissues.P hosphoinositides (PIs) are essential components of cellular membranes in eukaryotes. Though these specialized lipids comprise less than 1% of the cellular lipid cohort, they play key roles in many fundamental biological processes (Di Paolo and De Camilli 2006;Saarikangas et al. 2010). PIs possess such far ranging roles by serving as specialized membrane docking sites for effectors of numerous cellular signal transduction cascades. PIs also serve as precursors of lipid second messengers. They are concentrated on the cytosolic face of cellular membranes (Fig. 1A) and rapidly diffuse within the plane of the membrane. Reversible phosphorylation of the myo-inositol head group of phosphatidylinositol (PtdIns) at positions 3, 4, and 5 (Fig. 1B) gives rise to the seven PI isoforms identified in eukaryotic cells. PtdIns(4)P and PtdIns(4,5)P 2 are constitutively present in membranes and comprise the largest pool of cellular PIs, whereas PtdIns(3,4,5)P 3 is essentially undetectable in most types of unstimulated cells (Lemmon and Ferguson 2000;Saarikangas et al. 2010).The spatiotemporally regulated production and turnover of phosphoinositides is crucial for localized PI signaling and function. Numerous phosphatidylinositol kinases and phosphatases are involved in regulating the metabolism of the various PI isoforms (Fig. 1)

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“…Thus, the correct spatial and temporal regulation of these enzymes is of central importance (1,2). As a consequence, not only the lack of these enzymes but also the disruption of their interactions can have profound effects on cell function and result in pathological conditions (2)(3)(4)(5)(6)(7)(8)(9).…”

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confidence: 99%

Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1

Swan

Tomasini

Pirruccello

et al. 2010

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

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117

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Mutations of the inositol 5′ phosphatase oculocerebrorenal syndrome of Lowe (OCRL) give rise to the congenital X-linked disorders oculocerebrorenal syndrome of Lowe and Dent disease, two conditions giving rise to abnormal kidney proximal tubule reabsorption, and additional nervous system and ocular defects in the case of Lowe syndrome. Here, we identify two closely related endocytic proteins, Ses1 and Ses2, which interact with the ASH-RhoGAP-like (ASPM-SPD-2-Hydin homology and Rho-GTPase Activating Domain-like) domain of OCRL. The interaction is mediated by a short amino acid motif similar to that used by the rab-5 effector APPL1 (Adaptor Protein containing pleckstrin homology [PH] domain, PTB domain and Leucine zipper motif 1) APPL1 for OCRL binding. Ses binding is mutually exclusive with APPL1 binding, and is disrupted by the same missense mutations in the ASHRhoGAP-like domain that also disrupt APPL1 binding. Like APPL1, Ses1 and -2 are localized on endosomes but reside on different endosomal subpopulations. These findings define a consensus motif (which we have called a phenylalanine and histidine [F&H] motif) for OCRL binding and are consistent with a scenario in which Lowe syndrome and Dent disease result from perturbations at multiple sites within the endocytic pathway.Dent disease | endocytosis | Lowe syndrome I nositol phospholipids play a critical regulatory function in cell physiology, including membrane traffic. The interconversion of different phosphoinositide species via the action of kinases and phosphatases plays a key role in the maturation and progression of membranes through different stations of the exocytic and endocytic pathways, coordinating these processes with signaling reactions. Thus, the correct spatial and temporal regulation of these enzymes is of central importance (1, 2). As a consequence, not only the lack of these enzymes but also the disruption of their interactions can have profound effects on cell function and result in pathological conditions (2-9).Two human diseases are caused by mutations in an enzyme that selectively dephosphorylates the inositol ring at the 5′ position, using phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ], two phosphoinositides concentrated in the plasma membrane, as its preferred substrates (10). One such disease is oculocerebrorenal syndrome of Lowe (hence the enzyme name "OCRL") (3, 11). This condition, also referred to as "Lowe syndrome," is a severe X-linked disorder characterized by congenital cataracts (12), kidney readsorption defects caused by proximal tubule dysfunction, cognitive impairment, muscle hypotonia, and autism spectrum behavioral disorders (13,14). The other condition is Dent disease, an X-linked disorder involving kidney defects very similar to those associated with Lowe syndrome but, for reasons not yet known, few other dysfunctions (15)(16)(17)(18)(19).OCRL comprises an N-terminal Pleckstrin Homology (PH) domain followed in sequence by a central inositol 5′-phospha...

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Mutations in Phosphoinositide Metabolizing Enzymes and Human Disease

Cited by 163 publications

References 110 publications

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

Phosphoinositides in Cell Architecture

Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1

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