Free IL-12p40 monomer is a polyfunctional adaptor for generating novel IL-12-like heterodimers extracellularly
IL-12p40 partners with the p35 and p19 polypeptides to generate the heterodimeric cytokines IL-12 and IL-23, respectively. These cytokines play critical and distinct roles in host defense. The assembly of these heterodimers is thought to take place within the cell, resulting in the secretion of full...
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Veröffentlicht in: | The Journal of immunology (1950) 2014-06, Vol.192 (12), p.6028-6036 |
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container_title | The Journal of immunology (1950) |
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creator | Abdi, Kaveh Singh, Nevil J Spooner, Eric Kessler, Benedikt M Radaev, Sergei Lantz, Larry Xiao, Tsan Sam Matzinger, Polly Sun, Peter D Ploegh, Hidde L |
description | IL-12p40 partners with the p35 and p19 polypeptides to generate the heterodimeric cytokines IL-12 and IL-23, respectively. These cytokines play critical and distinct roles in host defense. The assembly of these heterodimers is thought to take place within the cell, resulting in the secretion of fully functional cytokines. Although the p40 subunit alone can also be rapidly secreted in response to inflammatory signals, its biological significance remains unclear. In this article, we show that the secreted p40 monomer can generate de novo IL-12-like activities by combining extracellularly with p35 released from other cells. Surprisingly, an unbiased proteomic analysis reveals multiple such extracellular binding partners for p40 in the serum of mice after an endotoxin challenge. We biochemically validate the binding of one of these novel partners, the CD5 Ag-like glycoprotein, to the p40 monomer. Nevertheless, the assembled p40-CD5L heterodimer does not recapitulate the biological activity of IL-12. These findings underscore the plasticity of secreted free p40 monomer, suggesting that p40 functions as an adaptor that is able to generate multiple de novo composites in combination with other locally available polypeptide partners after secretion. |
doi_str_mv | 10.4049/jimmunol.1400159 |
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These cytokines play critical and distinct roles in host defense. The assembly of these heterodimers is thought to take place within the cell, resulting in the secretion of fully functional cytokines. Although the p40 subunit alone can also be rapidly secreted in response to inflammatory signals, its biological significance remains unclear. In this article, we show that the secreted p40 monomer can generate de novo IL-12-like activities by combining extracellularly with p35 released from other cells. Surprisingly, an unbiased proteomic analysis reveals multiple such extracellular binding partners for p40 in the serum of mice after an endotoxin challenge. We biochemically validate the binding of one of these novel partners, the CD5 Ag-like glycoprotein, to the p40 monomer. Nevertheless, the assembled p40-CD5L heterodimer does not recapitulate the biological activity of IL-12. These findings underscore the plasticity of secreted free p40 monomer, suggesting that p40 functions as an adaptor that is able to generate multiple de novo composites in combination with other locally available polypeptide partners after secretion.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.1400159</identifier><identifier>PMID: 24821971</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Apoptosis Regulatory Proteins - genetics ; Apoptosis Regulatory Proteins - immunology ; CD5 Antigens - genetics ; CD5 Antigens - immunology ; Dimerization ; Interleukin-12 - genetics ; Interleukin-12 - immunology ; Mice ; Mice, Knockout ; Proteomics ; Receptors, Immunologic - genetics ; Receptors, Immunologic - immunology ; Receptors, Scavenger</subject><ispartof>The Journal of immunology (1950), 2014-06, Vol.192 (12), p.6028-6036</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c370t-e128c5346301e760bb6c84b6cb5ac6c76658a1755292c4e34cfa48d4cc1dff3e3</citedby><cites>FETCH-LOGICAL-c370t-e128c5346301e760bb6c84b6cb5ac6c76658a1755292c4e34cfa48d4cc1dff3e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24821971$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Abdi, Kaveh</creatorcontrib><creatorcontrib>Singh, Nevil J</creatorcontrib><creatorcontrib>Spooner, Eric</creatorcontrib><creatorcontrib>Kessler, Benedikt M</creatorcontrib><creatorcontrib>Radaev, Sergei</creatorcontrib><creatorcontrib>Lantz, Larry</creatorcontrib><creatorcontrib>Xiao, Tsan Sam</creatorcontrib><creatorcontrib>Matzinger, Polly</creatorcontrib><creatorcontrib>Sun, Peter D</creatorcontrib><creatorcontrib>Ploegh, Hidde L</creatorcontrib><title>Free IL-12p40 monomer is a polyfunctional adaptor for generating novel IL-12-like heterodimers extracellularly</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>IL-12p40 partners with the p35 and p19 polypeptides to generate the heterodimeric cytokines IL-12 and IL-23, respectively. These cytokines play critical and distinct roles in host defense. The assembly of these heterodimers is thought to take place within the cell, resulting in the secretion of fully functional cytokines. Although the p40 subunit alone can also be rapidly secreted in response to inflammatory signals, its biological significance remains unclear. In this article, we show that the secreted p40 monomer can generate de novo IL-12-like activities by combining extracellularly with p35 released from other cells. Surprisingly, an unbiased proteomic analysis reveals multiple such extracellular binding partners for p40 in the serum of mice after an endotoxin challenge. We biochemically validate the binding of one of these novel partners, the CD5 Ag-like glycoprotein, to the p40 monomer. Nevertheless, the assembled p40-CD5L heterodimer does not recapitulate the biological activity of IL-12. These findings underscore the plasticity of secreted free p40 monomer, suggesting that p40 functions as an adaptor that is able to generate multiple de novo composites in combination with other locally available polypeptide partners after secretion.</description><subject>Animals</subject><subject>Apoptosis Regulatory Proteins - genetics</subject><subject>Apoptosis Regulatory Proteins - immunology</subject><subject>CD5 Antigens - genetics</subject><subject>CD5 Antigens - immunology</subject><subject>Dimerization</subject><subject>Interleukin-12 - genetics</subject><subject>Interleukin-12 - immunology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Proteomics</subject><subject>Receptors, Immunologic - genetics</subject><subject>Receptors, Immunologic - immunology</subject><subject>Receptors, Scavenger</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkT1PwzAQhi0EglLYmZBHlsD5M-mIKgpIlVhgjlznUlIcO9gJov-eoLbMDHe3vPfodA8hVwxuJcjZ3aZp28EHd8skAFOzIzJhSkGmNehjMgHgPGO5zs_IeUobANDA5Sk547LgbJazCfGLiEiflxnjnQTaBh9ajLRJ1NAuuG09eNs3wRtHTWW6PkRaj7VGj9H0jV9TH77Q7QiZaz6QvmOPMVTNyEkUv_toLDo3OBPd9oKc1MYlvNzPKXlbPLzOn7Lly-Pz_H6ZWZFDnyHjhVVCagEMcw2rlbaFHNtKGattrrUqDMuV4jNuJQppayOLSlrLqroWKKbkZsftYvgcMPVl26TfM4zHMKRy_BLTEoRm_4gKKXPFlRqjsIvaGFKKWJddbFoTtyWD8ldIeRBS7oWMK9d7-rBqsfpbOBgQP5NIiKE</recordid><startdate>20140615</startdate><enddate>20140615</enddate><creator>Abdi, Kaveh</creator><creator>Singh, Nevil J</creator><creator>Spooner, Eric</creator><creator>Kessler, Benedikt M</creator><creator>Radaev, Sergei</creator><creator>Lantz, Larry</creator><creator>Xiao, Tsan Sam</creator><creator>Matzinger, Polly</creator><creator>Sun, Peter D</creator><creator>Ploegh, Hidde L</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope></search><sort><creationdate>20140615</creationdate><title>Free IL-12p40 monomer is a polyfunctional adaptor for generating novel IL-12-like heterodimers extracellularly</title><author>Abdi, Kaveh ; Singh, Nevil J ; Spooner, Eric ; Kessler, Benedikt M ; Radaev, Sergei ; Lantz, Larry ; Xiao, Tsan Sam ; Matzinger, Polly ; Sun, Peter D ; Ploegh, Hidde L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c370t-e128c5346301e760bb6c84b6cb5ac6c76658a1755292c4e34cfa48d4cc1dff3e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Apoptosis Regulatory Proteins - genetics</topic><topic>Apoptosis Regulatory Proteins - immunology</topic><topic>CD5 Antigens - genetics</topic><topic>CD5 Antigens - immunology</topic><topic>Dimerization</topic><topic>Interleukin-12 - genetics</topic><topic>Interleukin-12 - immunology</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Proteomics</topic><topic>Receptors, Immunologic - genetics</topic><topic>Receptors, Immunologic - immunology</topic><topic>Receptors, Scavenger</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Abdi, Kaveh</creatorcontrib><creatorcontrib>Singh, Nevil J</creatorcontrib><creatorcontrib>Spooner, Eric</creatorcontrib><creatorcontrib>Kessler, Benedikt M</creatorcontrib><creatorcontrib>Radaev, Sergei</creatorcontrib><creatorcontrib>Lantz, Larry</creatorcontrib><creatorcontrib>Xiao, Tsan Sam</creatorcontrib><creatorcontrib>Matzinger, Polly</creatorcontrib><creatorcontrib>Sun, Peter D</creatorcontrib><creatorcontrib>Ploegh, Hidde L</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>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Abdi, Kaveh</au><au>Singh, Nevil J</au><au>Spooner, Eric</au><au>Kessler, Benedikt M</au><au>Radaev, Sergei</au><au>Lantz, Larry</au><au>Xiao, Tsan Sam</au><au>Matzinger, Polly</au><au>Sun, Peter D</au><au>Ploegh, Hidde L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Free IL-12p40 monomer is a polyfunctional adaptor for generating novel IL-12-like heterodimers extracellularly</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2014-06-15</date><risdate>2014</risdate><volume>192</volume><issue>12</issue><spage>6028</spage><epage>6036</epage><pages>6028-6036</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>IL-12p40 partners with the p35 and p19 polypeptides to generate the heterodimeric cytokines IL-12 and IL-23, respectively. These cytokines play critical and distinct roles in host defense. The assembly of these heterodimers is thought to take place within the cell, resulting in the secretion of fully functional cytokines. Although the p40 subunit alone can also be rapidly secreted in response to inflammatory signals, its biological significance remains unclear. In this article, we show that the secreted p40 monomer can generate de novo IL-12-like activities by combining extracellularly with p35 released from other cells. Surprisingly, an unbiased proteomic analysis reveals multiple such extracellular binding partners for p40 in the serum of mice after an endotoxin challenge. We biochemically validate the binding of one of these novel partners, the CD5 Ag-like glycoprotein, to the p40 monomer. Nevertheless, the assembled p40-CD5L heterodimer does not recapitulate the biological activity of IL-12. These findings underscore the plasticity of secreted free p40 monomer, suggesting that p40 functions as an adaptor that is able to generate multiple de novo composites in combination with other locally available polypeptide partners after secretion.</abstract><cop>United States</cop><pmid>24821971</pmid><doi>10.4049/jimmunol.1400159</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Apoptosis Regulatory Proteins - genetics Apoptosis Regulatory Proteins - immunology CD5 Antigens - genetics CD5 Antigens - immunology Dimerization Interleukin-12 - genetics Interleukin-12 - immunology Mice Mice, Knockout Proteomics Receptors, Immunologic - genetics Receptors, Immunologic - immunology Receptors, Scavenger |
title | Free IL-12p40 monomer is a polyfunctional adaptor for generating novel IL-12-like heterodimers extracellularly |
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