B‐cell‐intrinsic function of TAPP adaptors in controlling germinal center responses and autoantibody production in mice

Jayachandran, Nipun; Landego, Ivan; Hou, Sen; Alessi, Dario R.; Marshall, Aaron J.

doi:10.1002/eji.201646596

Cited by 10 publications

(13 citation statements)

References 53 publications

(89 reference statements)

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“…Because c-myc and PI3K signaling are both essential for GC responses and have been associated with GC B cell selection in the light zone (39,40), it is tempting to speculate that PI3K-and c-myc-dependent activation of glycolysis may help provide a selective growth advantage to high-affinity B cells receiving BCR and T FH cell signals. It is possible that deregulation of glucose transport in TAPP KI mice may allow survival and differentiation of GC B cells that would normally be uncompetitive, accounting for previously observed increases in GC size, polyclonal IgG production and autoantibody production (20,21).…”

Section: Discussionmentioning

confidence: 99%

“…We previously found that TAPP KI mice develop lupus-like autoimmunity associated with dysregulated GCs (20). Because GC B cells in TAPP KI mice express higher levels of GLUT1 and show elevated glucose uptake, we assessed whether inhibition of glycolysis has any effect on the chronic GCs in middle-aged TAPP KI mice.…”

Section: Impact Of 2-dg Treatment On B Cell Proliferation Chronic Gcmentioning

confidence: 99%

“…Mice, in which TAPP adaptors are incapable of binding PI(3,4)P2, were generated by introducing point mutations to TAPP1 and TAPP2 genes, resulting in arginineto-leucine substitutions within their respective PI-binding pockets (19). These TAPP knock in (KI) mice exhibit markedly elevated serum Ab titers and chronic GCs, and they develop exaggerated GC responses upon immunization (20,21). TAPP KI mice also develop autoimmunity with age, which can be driven by TAPP KI B cells within a wild-type (WT) genetic background (20).…”

mentioning

confidence: 99%

“…These TAPP knock in (KI) mice exhibit markedly elevated serum Ab titers and chronic GCs, and they develop exaggerated GC responses upon immunization (20,21). TAPP KI mice also develop autoimmunity with age, which can be driven by TAPP KI B cells within a wild-type (WT) genetic background (20). In this study, we find that uncoupling of TAPP adaptors from PI(3,4)P2 results in elevated activation of Akt and markedly elevated metabolic activity, including increased glycolysis, glucose transport, and glucose transporter expression.…”

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confidence: 99%

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TAPP Adaptors Control B Cell Metabolism by Modulating the Phosphatidylinositol 3-Kinase Signaling Pathway: A Novel Regulatory Circuit Preventing Autoimmunity

Jayachandran

Mejia

Sheikholeslami

et al. 2018

The Journal of Immunology

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Class I PI3K enzymes play critical roles in B cell activation by phosphorylating plasma membrane lipids to generate two distinct phosphoinositide (PI) products, PI(3,4,5)P3 and PI(3,4)P2. These PIs each bind distinct but overlapping sets of intracellular proteins that control cell survival, cytoskeletal reorganization, and metabolic activity. The tandem PH domain containing proteins (TAPPs) bind with high specificity to PI(3,4)P2, and their genetic uncoupling from PI(3,4)P2 in TAPP knock in (KI) mice was previously found to cause chronic B cell activation, abnormal germinal centers (GCs), and autoimmunity. In this article, we find that TAPPs provide feedback regulation affecting PI3K signaling and metabolic activation of B cells. Upon activation, TAPP KI B cells show enhanced metabolic activity associated with increased extracellular acidification rate, increased expression of glucose transporter GLUT1, and increased glucose uptake. TAPP KI B cells show markedly increased activation of the PI3K-regulated kinases Akt, GSK3β, and p70-S6K. Conversely, overexpression of the C-terminal TAPP PH domains in B cells can inhibit Akt phosphorylation by a mechanism requiring the TAPP PI(3,4)P2-binding pocket. Inhibition of the PI3K pathway in TAPP KI B cells reduced GLUT1 expression and glucose uptake, whereas inhibition of Akt alone was not sufficient to normalize these responses. TAPP KI GC B cells also show increased GLUT1 and glucose uptake, and treatment with the inhibitor of glycolysis 2-deoxy-D-glucose reduced chronic GC responses and autoantibody production within these mice. Our findings show that TAPP-PI(3,4)P2 interaction controls activation of glycolysis and highlights the significance of this pathway for B cell activation, GC responses, and autoimmunity.

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Section: Discussionmentioning

confidence: 99%

Section: Impact Of 2-dg Treatment On B Cell Proliferation Chronic Gcmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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TAPP Adaptors Control B Cell Metabolism by Modulating the Phosphatidylinositol 3-Kinase Signaling Pathway: A Novel Regulatory Circuit Preventing Autoimmunity

Jayachandran

Mejia

Sheikholeslami

et al. 2018

The Journal of Immunology

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“…Deletion of SHIP in BCR‐transgenic B cells specific for Ars or HEL antigens was found to reverse their anergic phenotype in two models of self‐tolerance . We found that B cells bearing mutations uncoupling the TAPP adaptors from PI(3,4)P 2 were hyper‐active and drive an SLE‐like phenotype , suggesting that proteins binding this SHIP enzymatic product may contribute important regulatory functions. The function of SHIP in maintaining B‐cell tolerance and preventing autoimmunity may be related to its interaction with FcγRIIB, as FcγRIIB deletion in some mouse strains can also cause lupus‐like autoimmunity, but interestingly not the C57BL/6 background used for the above B cell‐specific SHIP deletion studies .…”

Section: Introductionmentioning

confidence: 86%

Regulation of immune cell signaling by SHIP1: A phosphatase, scaffold protein, and potential therapeutic target

2017

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The phosphoinositide phosphatase SHIP is a critical regulator of immune cell activation. Despite considerable study, the mechanisms controlling SHIP activity to ensure balanced cell activation remain incompletely understood. SHIP dampens BCR signaling in part through its association with the inhibitory coreceptor Fc gamma receptor IIB, and serves as an effector for other inhibitory receptors in various immune cell types. The established paradigm emphasizes SHIP's inhibitory receptor‐dependent function in regulating phosphoinositide 3‐kinase signaling by dephosphorylating the phosphoinositide PI(3,4,5)P3; however, substantial evidence indicates that SHIP can be activated independently of inhibitory receptors and can function as an intrinsic brake on activation signaling. Here, we integrate historical and recent reports addressing the regulation and function of SHIP in immune cells, which together indicate that SHIP acts as a multifunctional protein controlled by multiple regulatory inputs, and influences downstream signaling via both phosphatase‐dependent and ‐independent means. We further summarize accumulated evidence regarding the functions of SHIP in B cells, T cells, NK cells, dendritic cells, mast cells, and macrophages, and data suggesting defective expression or activity of SHIP in autoimmune and malignant disorders. Lastly, we discuss the biological activities, therapeutic promise, and limitations of small molecule modulators of SHIP enzymatic activity.

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Identification of PtdIns(3,4)P2 effectors in human platelets using quantitative proteomics

Durrant

Moore

Bayliss

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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After decades in PtdIns(3,4,5)P 3 's shadow, PtdIns(3,4)P 2 has now emerged as a bona fide regulator of important cellular events, including endocytosis and cell migration. New understanding of PtdIns(3,4)P 2 's cellular roles has been possible via novel approaches to observe and quantify cellular PtdIns(3,4)P 2 dynamics, alongside methods to target the kinases and phosphatases governing phosphoinositide turnover. Despite this, the mechanisms by which PtdIns(3,4)P 2 orchestrates its cellular roles remain more poorly understood, most notably because, to date, few PtdIns(3,4)P 2 effectors have been identified. Here, we develop and apply an affinity-proteomics strategy to conduct a global screen for PtdIns(3,4)P 2 interactors in human platelets; a primary cell type with striking PtdIns(3,4)P 2 accumulation. Through an integrated approach, coupling affinity capture of PtdIns(3,4)P 2 -binding proteins to both label-free and isobaric tag-based quantitative proteomics, we identify a diverse PtdIns(3,4)P 2 interactome. Included are long-established PtdIns(3,4)P 2 -binding proteins such as PLEKHA1, PLEKHA2, AKT and DAPP1, and a host of potentially novel effectors, including MTMR5, PNKD, RASA3 and GAB3. The PtdIns(3,4)P 2 interactome shows an enrichment of pleckstrin homology (PH) domain-containing proteins, and through bioinformatics and array analyses we characterise the PH domain of MTMR5 and define its phosphoinositide selectivity. The interactome is also diverse in function, including several proteins known to support protein trafficking and cytoskeletal mobilisation. Such proteins have the ability to drive key platelet events, and to fulfil recently-defined roles for PtdIns(3,4)P 2 in a wider range of cell types. Moreover, this study will serve as a valuable resource for the future characterisation of effector-driven PtdIns(3,4)P 2 function.

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B‐cell‐intrinsic function of TAPP adaptors in controlling germinal center responses and autoantibody production in mice

Cited by 10 publications

References 53 publications

TAPP Adaptors Control B Cell Metabolism by Modulating the Phosphatidylinositol 3-Kinase Signaling Pathway: A Novel Regulatory Circuit Preventing Autoimmunity

TAPP Adaptors Control B Cell Metabolism by Modulating the Phosphatidylinositol 3-Kinase Signaling Pathway: A Novel Regulatory Circuit Preventing Autoimmunity

Regulation of immune cell signaling by SHIP1: A phosphatase, scaffold protein, and potential therapeutic target

Identification of PtdIns(3,4)P2 effectors in human platelets using quantitative proteomics

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