Serine/threonine phosphatase PP2A is essential for optimal B cell function
Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, has been shown to control T cell function. We found that in vitro-activated B cells and B cells from various lupus-prone mice and patients with systemic lupus erythematosus display increased PP2A activity. To understand the contribution...
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| creator | Meidan, Esra Li, Hao Pan, Wenliang Kono, Michihito Yu, Shuilian Kyttaris, Vasileios C Ioannidis, Christina Rodriguez Rodriguez, Noe Crispin, Jose C Apostolidis, Sokratis A Lee, Pui Manis, John Sharabi, Amir Tsokos, Maria G Tsokos, George C |
| description | Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, has been shown to control T cell function. We found that in vitro-activated B cells and B cells from various lupus-prone mice and patients with systemic lupus erythematosus display increased PP2A activity. To understand the contribution of PP2A to B cell function, we generated a Cd19CrePpp2r1afl/fl (flox/flox) mouse which lacks functional PP2A only in B cells. Flox/flox mice displayed reduced spontaneous germinal center formation and decreased responses to T cell-dependent and T-independent antigens, while their B cells responded poorly in vitro to stimulation with an anti-CD40 antibody or CpG in the presence of IL-4. Transcriptome and metabolome studies revealed altered nicotinamide adenine dinucleotide (NAD) and purine/pyrimidine metabolism and increased expression of purine nucleoside phosphorylase in PP2A-deficient B cells. Our results demonstrate that PP2A is required for optimal B cell function and may contribute to increased B cell activity in systemic autoimmunity. |
| doi_str_mv | 10.1172/jci.insight.130655 |
| format | Article |
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We found that in vitro-activated B cells and B cells from various lupus-prone mice and patients with systemic lupus erythematosus display increased PP2A activity. To understand the contribution of PP2A to B cell function, we generated a Cd19CrePpp2r1afl/fl (flox/flox) mouse which lacks functional PP2A only in B cells. Flox/flox mice displayed reduced spontaneous germinal center formation and decreased responses to T cell-dependent and T-independent antigens, while their B cells responded poorly in vitro to stimulation with an anti-CD40 antibody or CpG in the presence of IL-4. Transcriptome and metabolome studies revealed altered nicotinamide adenine dinucleotide (NAD) and purine/pyrimidine metabolism and increased expression of purine nucleoside phosphorylase in PP2A-deficient B cells. Our results demonstrate that PP2A is required for optimal B cell function and may contribute to increased B cell activity in systemic autoimmunity.</description><identifier>ISSN: 2379-3708</identifier><identifier>EISSN: 2379-3708</identifier><identifier>DOI: 10.1172/jci.insight.130655</identifier><identifier>PMID: 32161189</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Animals ; Autoantibodies - biosynthesis ; Autoimmunity ; B-Lymphocytes - enzymology ; B-Lymphocytes - immunology ; Case-Control Studies ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Germinal Center - immunology ; Humans ; Lupus Erythematosus, Systemic - enzymology ; Lupus Erythematosus, Systemic - immunology ; Lymphocyte Activation ; Mice ; Mice, Transgenic ; Protein Phosphatase 2 - metabolism ; T-Lymphocytes - immunology</subject><ispartof>JCI insight, 2020-03, Vol.5 (5)</ispartof><rights>2020 American Society for Clinical Investigation 2020 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3175-e5d99e366ce86dc023c3b64791c5ab9c45eea61b64baccd4c7ef7bfe5ab284893</citedby><cites>FETCH-LOGICAL-c3175-e5d99e366ce86dc023c3b64791c5ab9c45eea61b64baccd4c7ef7bfe5ab284893</cites><orcidid>0000-0002-6242-6774 ; 0000-0002-7590-3621 ; 0000-0002-2171-8826 ; 0000-0002-7663-534X ; 0000-0001-9589-2360 ; 0000-0001-7652-3826 ; 0000-0002-0224-0097</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141385/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141385/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32161189$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Meidan, Esra</creatorcontrib><creatorcontrib>Li, Hao</creatorcontrib><creatorcontrib>Pan, Wenliang</creatorcontrib><creatorcontrib>Kono, Michihito</creatorcontrib><creatorcontrib>Yu, Shuilian</creatorcontrib><creatorcontrib>Kyttaris, Vasileios C</creatorcontrib><creatorcontrib>Ioannidis, Christina</creatorcontrib><creatorcontrib>Rodriguez Rodriguez, Noe</creatorcontrib><creatorcontrib>Crispin, Jose C</creatorcontrib><creatorcontrib>Apostolidis, Sokratis A</creatorcontrib><creatorcontrib>Lee, Pui</creatorcontrib><creatorcontrib>Manis, John</creatorcontrib><creatorcontrib>Sharabi, Amir</creatorcontrib><creatorcontrib>Tsokos, Maria G</creatorcontrib><creatorcontrib>Tsokos, George C</creatorcontrib><title>Serine/threonine phosphatase PP2A is essential for optimal B cell function</title><title>JCI insight</title><addtitle>JCI Insight</addtitle><description>Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, has been shown to control T cell function. 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Li, Hao ; Pan, Wenliang ; Kono, Michihito ; Yu, Shuilian ; Kyttaris, Vasileios C ; Ioannidis, Christina ; Rodriguez Rodriguez, Noe ; Crispin, Jose C ; Apostolidis, Sokratis A ; Lee, Pui ; Manis, John ; Sharabi, Amir ; Tsokos, Maria G ; Tsokos, George C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3175-e5d99e366ce86dc023c3b64791c5ab9c45eea61b64baccd4c7ef7bfe5ab284893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Autoantibodies - biosynthesis</topic><topic>Autoimmunity</topic><topic>B-Lymphocytes - enzymology</topic><topic>B-Lymphocytes - immunology</topic><topic>Case-Control Studies</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Flow Cytometry</topic><topic>Germinal Center - immunology</topic><topic>Humans</topic><topic>Lupus Erythematosus, Systemic - enzymology</topic><topic>Lupus Erythematosus, Systemic - immunology</topic><topic>Lymphocyte Activation</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Protein Phosphatase 2 - metabolism</topic><topic>T-Lymphocytes - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Meidan, Esra</creatorcontrib><creatorcontrib>Li, Hao</creatorcontrib><creatorcontrib>Pan, Wenliang</creatorcontrib><creatorcontrib>Kono, Michihito</creatorcontrib><creatorcontrib>Yu, Shuilian</creatorcontrib><creatorcontrib>Kyttaris, Vasileios C</creatorcontrib><creatorcontrib>Ioannidis, Christina</creatorcontrib><creatorcontrib>Rodriguez Rodriguez, Noe</creatorcontrib><creatorcontrib>Crispin, Jose C</creatorcontrib><creatorcontrib>Apostolidis, Sokratis A</creatorcontrib><creatorcontrib>Lee, Pui</creatorcontrib><creatorcontrib>Manis, John</creatorcontrib><creatorcontrib>Sharabi, Amir</creatorcontrib><creatorcontrib>Tsokos, Maria G</creatorcontrib><creatorcontrib>Tsokos, George C</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>JCI insight</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Meidan, Esra</au><au>Li, Hao</au><au>Pan, Wenliang</au><au>Kono, Michihito</au><au>Yu, Shuilian</au><au>Kyttaris, Vasileios C</au><au>Ioannidis, Christina</au><au>Rodriguez Rodriguez, Noe</au><au>Crispin, Jose C</au><au>Apostolidis, Sokratis A</au><au>Lee, Pui</au><au>Manis, John</au><au>Sharabi, Amir</au><au>Tsokos, Maria G</au><au>Tsokos, George C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Serine/threonine phosphatase PP2A is essential for optimal B cell function</atitle><jtitle>JCI insight</jtitle><addtitle>JCI Insight</addtitle><date>2020-03-12</date><risdate>2020</risdate><volume>5</volume><issue>5</issue><issn>2379-3708</issn><eissn>2379-3708</eissn><abstract>Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, has been shown to control T cell function. We found that in vitro-activated B cells and B cells from various lupus-prone mice and patients with systemic lupus erythematosus display increased PP2A activity. To understand the contribution of PP2A to B cell function, we generated a Cd19CrePpp2r1afl/fl (flox/flox) mouse which lacks functional PP2A only in B cells. Flox/flox mice displayed reduced spontaneous germinal center formation and decreased responses to T cell-dependent and T-independent antigens, while their B cells responded poorly in vitro to stimulation with an anti-CD40 antibody or CpG in the presence of IL-4. Transcriptome and metabolome studies revealed altered nicotinamide adenine dinucleotide (NAD) and purine/pyrimidine metabolism and increased expression of purine nucleoside phosphorylase in PP2A-deficient B cells. 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| subjects | Animals Autoantibodies - biosynthesis Autoimmunity B-Lymphocytes - enzymology B-Lymphocytes - immunology Case-Control Studies Enzyme-Linked Immunosorbent Assay Flow Cytometry Germinal Center - immunology Humans Lupus Erythematosus, Systemic - enzymology Lupus Erythematosus, Systemic - immunology Lymphocyte Activation Mice Mice, Transgenic Protein Phosphatase 2 - metabolism T-Lymphocytes - immunology |
| title | Serine/threonine phosphatase PP2A is essential for optimal B cell function |
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