{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:28:50Z","timestamp":1791419330551,"version":"4.3.3"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2018,7,1]],"date-time":"2018-07-01T00:00:00Z","timestamp":1530403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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, GSK3\u03b2, 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\u2013PI(3,4)P2 interaction controls activation of glycolysis and highlights the significance of this pathway for B cell activation, GC responses, and autoimmunity.<\/jats:p>","DOI":"10.4049\/jimmunol.1701440","type":"journal-article","created":{"date-parts":[[2018,6,8]],"date-time":"2018-06-08T16:25:17Z","timestamp":1528475117000},"page":"406-416","source":"Crossref","is-referenced-by-count":61,"title":["TAPP Adaptors Control B Cell Metabolism by Modulating the Phosphatidylinositol 3-Kinase Signaling Pathway: A Novel Regulatory Circuit Preventing Autoimmunity"],"prefix":"10.1093","volume":"201","author":[{"given":"Nipun","family":"Jayachandran","sequence":"first","affiliation":[{"name":"Department of Immunology, University of Manitoba , Winnipeg, Manitoba R3E 0T5 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgard M","family":"Mejia","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Manitoba , Winnipeg, Manitoba R3E 0T5 ,","place":["Canada"]},{"name":"Department of Pharmacology and Therapeutics, University of Manitoba , Winnipeg, Manitoba R3E 0T6 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimia","family":"Sheikholeslami","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Manitoba , Winnipeg, Manitoba R3E 0T5 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6988-1139","authenticated-orcid":false,"given":"Affan A","family":"Sher","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Manitoba , Winnipeg, Manitoba R3E 0T5 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8287-8981","authenticated-orcid":false,"given":"Sen","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Manitoba , Winnipeg, Manitoba R3E 0T5 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant M","family":"Hatch","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, University of Manitoba , Winnipeg, Manitoba R3E 0T6 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1175-5498","authenticated-orcid":false,"given":"Aaron J","family":"Marshall","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Manitoba , Winnipeg, Manitoba R3E 0T5 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,7,15]]},"reference":[{"key":"2025030417570343800_r1","doi-asserted-by":"crossref","first-page":"1242454","DOI":"10.1126\/science.1242454","article-title":"Fueling immunity: insights into metabolism and lymphocyte function","volume":"342","author":"Pearce","year":"2013","journal-title":"Science"},{"key":"2025030417570343800_r2","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/nri.2016.70","article-title":"A guide to immunometabolism for immunologists","volume":"16","author":"O\u2019Neill","year":"2016","journal-title":"Nat. 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