{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T17:27:44Z","timestamp":1789147664787,"version":"build-2803163510"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T00:00:00Z","timestamp":1727049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32188101"],"award-info":[{"award-number":["32188101"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"State Key R&D Program of China","doi-asserted-by":"publisher","award":["2022YFA1304900"],"award-info":[{"award-number":["2022YFA1304900"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32070775"],"award-info":[{"award-number":["32070775"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>IL-7 is a cytokine produced by stromal cells, which binds to IL-7R\u03b1 and plays an important role for homeostasis of T lymphocytes. Excessive activities of IL-7\u2013triggered signaling pathways causes autoimmune diseases. How IL-7\u2013triggered signaling and immune effects are regulated is not fully understood. In this study, we show that the membrane-associated RING-CH (MARCH) E3 ligase family member MARCH8 mediates K27-linked polyubiquitination of IL-7R\u03b1, leading to its lysosomal degradation. Site-directed mutagenesis suggests that MARCH8 meditates polyubiquitination of IL-7R\u03b1 at K265\/K266, and mutation of these residues renders IL-7R\u03b1 resistance to MARCH8-mediated polyubiquitination and degradation. MARCH8 deficiency increases IL-7\u2013triggered activation of the downstream transcription factor STAT5 and transcriptional induction of the effector genes in human T lymphoma cells. MARCH8 deficiency also promotes IL-7\u2013triggered T cell proliferation and splenic memory CD8+ T cell differentiation in mice. Our findings suggest that MARCH8 negatively regulates IL-7\u2013triggered signaling by mediating K27-linked polyubiquitination and lysosomal degradation of IL-7R\u03b1, which reveals a negative regulatory mechanism of IL-7\u2013triggered T cell homeostasis.<\/jats:p>","DOI":"10.4049\/jimmunol.2400253","type":"journal-article","created":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T13:27:59Z","timestamp":1727098079000},"page":"1467-1478","source":"Crossref","is-referenced-by-count":7,"title":["MARCH8 Mediates K27-Linked Polyubiquitination of IL-7 Receptor \u03b1 to Negatively Regulate IL-7\u2013Triggered T Cell Homeostasis"],"prefix":"10.1093","volume":"213","author":[{"given":"Deng","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University , Wuhan ,","place":["China"]},{"name":"Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University , Wuhan ,","place":["China"]},{"name":"Research Unit of Innate Immune and Inflammatory Diseases (2019RU063), Chinese Academy of Medical Sciences , Wuhan ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Mei","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University , Wuhan ,","place":["China"]},{"name":"Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University , Wuhan ,","place":["China"]},{"name":"Research Unit of Innate Immune and Inflammatory Diseases (2019RU063), Chinese Academy of Medical Sciences , Wuhan ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University , Wuhan ,","place":["China"]},{"name":"Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University , Wuhan ,","place":["China"]},{"name":"Research Unit of Innate Immune and Inflammatory Diseases (2019RU063), Chinese Academy of Medical Sciences , Wuhan ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University , Wuhan ,","place":["China"]},{"name":"Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University , Wuhan ,","place":["China"]},{"name":"Research Unit of Innate Immune and Inflammatory Diseases (2019RU063), Chinese Academy of Medical Sciences , Wuhan ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Bing","family":"Shu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University , Wuhan ,","place":["China"]},{"name":"Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University , Wuhan ,","place":["China"]},{"name":"Research Unit of Innate Immune and Inflammatory Diseases (2019RU063), Chinese Academy of Medical Sciences , Wuhan ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,9,23]]},"reference":[{"key":"2025020609284073800_r1","doi-asserted-by":"crossref","first-page":"156049","DOI":"10.1016\/j.cyto.2022.156049","article-title":"IL-7: comprehensive review","volume":"160","author":"Winer","year":"2022","journal-title":"Cytokine"},{"key":"2025020609284073800_r2","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/j.0105-2896.2005.00234.x","article-title":"Interleukin-7 receptor \u03b1 (IL-7R\u03b1) deficiency: cellular and molecular bases. Analysis of clinical, immunological, and molecular features in 16 novel patients","volume":"203","author":"Giliani","year":"2005","journal-title":"Immunol. Rev."},{"key":"2025020609284073800_r3","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/3877","article-title":"Defective IL7R expression in T\u2212B+NK+ severe combined immunodeficiency","volume":"20","author":"Puel","year":"1998","journal-title":"Nat. Genet."},{"key":"2025020609284073800_r4","doi-asserted-by":"crossref","first-page":"2803","DOI":"10.1182\/blood.V96.8.2803","article-title":"A partial deficiency of interleukin-7R\u03b1 is sufficient to abrogate T-cell development and cause severe combined immunodeficiency","volume":"96","author":"Roifman","year":"2000","journal-title":"Blood"},{"key":"2025020609284073800_r5","doi-asserted-by":"crossref","first-page":"5610","DOI":"10.1073\/pnas.0308054101","article-title":"Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets","volume":"101","author":"Huster","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025020609284073800_r6","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1038\/ni1009","article-title":"Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells","volume":"4","author":"Kaech","year":"2003","journal-title":"Nat. Immunol."},{"key":"2025020609284073800_r7","first-page":"2131","article-title":"Interleukin-7 inhibits apoptosis of mouse malignant T-lymphoma cells by both suppressing the CPP32-like protease activation and inducing the Bcl-2 expression","volume":"13","author":"Lee","year":"1996","journal-title":"Oncogene"},{"key":"2025020609284073800_r8","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nri1052","article-title":"Cytokine control of memory T-cell development and survival","volume":"3","author":"Schluns","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"2025020609284073800_r9","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S1074-7613(00)80517-8","article-title":"The earliest T lineage\u2013committed cells depend on IL-7 for Bcl-2 expression and normal cell cycle progression","volume":"7","author":"von Freeden-Jeffry","year":"1997","journal-title":"Immunity"},{"key":"2025020609284073800_r10","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1084\/jem.181.4.1519","article-title":"Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine","volume":"181","author":"von Freeden-Jeffry","year":"1995","journal-title":"J. Exp. Med."},{"key":"2025020609284073800_r11","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1084\/jem.180.5.1955","article-title":"Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice","volume":"180","author":"Peschon","year":"1994","journal-title":"J. Exp. Med."},{"key":"2025020609284073800_r12","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/1074-7613(95)90047-0","article-title":"Defective lymphoid development in mice lacking expression of the common cytokine receptor \u03b3 chain","volume":"2","author":"Cao","year":"1995","journal-title":"Immunity"},{"key":"2025020609284073800_r13","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/S0092-8674(00)81166-6","article-title":"Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses","volume":"93","author":"Rodig","year":"1998","journal-title":"Cell"},{"key":"2025020609284073800_r14","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1093\/intimm\/12.2.123","article-title":"Janus kinase 3 (Jak3) is essential for common cytokine receptor \u03b3 chain (\u03b3c)-dependent signaling: comparative analysis of \u03b3c, Jak3, and \u03b3c and Jak3 double-deficient mice","volume":"12","author":"Suzuki","year":"2000","journal-title":"Int. Immunol."},{"key":"2025020609284073800_r15","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1097\/01.cji.0000210386.55951.c2","article-title":"IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells","volume":"29","author":"Rosenberg","year":"2006","journal-title":"J. Immunother."},{"key":"2025020609284073800_r16","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1084\/jem.20071681","article-title":"Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets","volume":"205","author":"Sport\u00e8s","year":"2008","journal-title":"J. Exp. Med."},{"key":"2025020609284073800_r17","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1093\/annonc\/mdv173","article-title":"ELYPSE-7: a randomized placebo-controlled phase IIa trial with CYT107 exploring the restoration of CD4+ lymphocyte count in lymphopenic metastatic breast cancer patients","volume":"26","author":"Tr\u00e9dan","year":"2015","journal-title":"Ann. Oncol."},{"key":"2025020609284073800_r18","doi-asserted-by":"crossref","first-page":"4882","DOI":"10.1182\/blood-2012-06-437236","article-title":"Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation","volume":"120","author":"Perales","year":"2012","journal-title":"Blood"},{"key":"2025020609284073800_r19","doi-asserted-by":"crossref","first-page":"6304","DOI":"10.1182\/blood-2008-10-186601","article-title":"IL-7 administration drives T cell\u2013cycle entry and expansion in HIV-1 infection","volume":"113","author":"Sereti","year":"2009","journal-title":"Blood"},{"key":"2025020609284073800_r20","doi-asserted-by":"crossref","first-page":"e98960","DOI":"10.1172\/jci.insight.98960","article-title":"Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial","volume":"3","author":"Francois","year":"2018","journal-title":"JCI Insight"},{"key":"2025020609284073800_r21","doi-asserted-by":"crossref","first-page":"e2319856121","DOI":"10.1073\/pnas.2319856121","article-title":"IL7 increases targeted lipid nanoparticle\u2013mediated mRNA expression in T cells in vitro and in vivo by enhancing T cell protein translation","volume":"121","author":"Tilsed","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025020609284073800_r22","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.cytogfr.2005.05.004","article-title":"Cell biology of IL-7, a key lymphotrophin","volume":"16","author":"Jiang","year":"2005","journal-title":"Cytokine Growth Factor Rev."},{"key":"2025020609284073800_r23","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1073\/pnas.1116582109","article-title":"Structural reorganization of the interleukin-7 signaling complex","volume":"109","author":"McElroy","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025020609284073800_r24","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/nri2023","article-title":"Interleukin-7 receptor expression: intelligent design","volume":"7","author":"Mazzucchelli","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"2025020609284073800_r25","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1002\/eji.1830240935","article-title":"Interleukin-7 induces the association of phosphatidylinositol 3-kinase with the \u03b1 chain of the interleukin-7 receptor","volume":"24","author":"Venkitaraman","year":"1994","journal-title":"Eur. J. Immunol."},{"key":"2025020609284073800_r26","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nri2970","article-title":"Harnessing the biology of IL-7 for therapeutic application","volume":"11","author":"Mackall","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"2025020609284073800_r27","doi-asserted-by":"crossref","first-page":"3269","DOI":"10.1182\/blood-2009-10-246876","article-title":"IL-7 induces rapid clathrin-mediated internalization and JAK3-dependent degradation of IL-7R\u03b1 in T cells","volume":"115","author":"Henriques","year":"2010","journal-title":"Blood"},{"key":"2025020609284073800_r28","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.3389\/fimmu.2019.01751","article-title":"The membrane-associated MARCH E3 ligase family: emerging roles in immune regulation","volume":"10","author":"Lin","year":"2019","journal-title":"Front. Immunol."},{"key":"2025020609284073800_r29","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.coi.2019.03.001","article-title":"MARCH ligases in immunity","volume":"58","author":"Liu","year":"2019","journal-title":"Curr. Opin. Immunol."},{"key":"2025020609284073800_r30","doi-asserted-by":"crossref","first-page":"12483","DOI":"10.1073\/pnas.1806217115","article-title":"MARCH3 attenuates IL-1\u03b2-triggered inflammation by mediating K48-linked polyubiquitination and degradation of IL-1RI","volume":"115","author":"Lin","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025020609284073800_r31","doi-asserted-by":"crossref","first-page":"14128","DOI":"10.1073\/pnas.1205246109","article-title":"The E3 ubiquitin ligase MARCH8 negatively regulates IL-1\u03b2-induced NF-\u03baB activation by targeting the IL1RAP coreceptor for ubiquitination and degradation","volume":"109","author":"Chen","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025020609284073800_r32","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41392-021-00834-7","article-title":"MARCH3 negatively regulates IL-3-triggered inflammatory response by mediating K48-linked polyubiquitination and degradation of IL-3R\u03b1","volume":"7","author":"Feng","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"2025020609284073800_r33","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1038\/s41423-021-00799-1","article-title":"The membrane-associated E3 ubiquitin ligase MARCH3 downregulates the IL-6 receptor and suppresses colitis-associated carcinogenesis","volume":"18","author":"Lin","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"2025020609284073800_r34","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1038\/s41423-022-00907-9","article-title":"The membrane-associated ubiquitin ligases MARCH2 and MARCH3 target IL-5 receptor alpha to negatively regulate eosinophilic airway inflammation","volume":"19","author":"Zeng","year":"2022","journal-title":"Cell. Mol. Immunol."},{"key":"2025020609284073800_r35","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1038\/s41422-023-00890-4","article-title":"PD-1 signaling negatively regulates the common cytokine receptor \u03b3 chain via MARCH5-mediated ubiquitination and degradation to suppress anti-tumor immunity","volume":"33","author":"Liu","year":"2023","journal-title":"Cell Res."},{"key":"2025020609284073800_r36","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/nmeth.3047","article-title":"Improved vectors and genome-wide libraries for CRISPR screening","volume":"11","author":"Sanjana","year":"2014","journal-title":"Nat. Methods"},{"key":"2025020609284073800_r37","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1126\/science.1247005","article-title":"Genome-scale CRISPR-Cas9 knockout screening in human cells","volume":"343","author":"Shalem","year":"2014","journal-title":"Science"},{"key":"2025020609284073800_r38","doi-asserted-by":"crossref","first-page":"53840","DOI":"10.1074\/jbc.M409662200","article-title":"Solution structure of the Kaposi\u2019s sarcoma-associated herpesvirus K3 N-terminal domain reveals a novel E2-binding C4HC3-type RING domain","volume":"279","author":"Dodd","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2025020609284073800_r39","doi-asserted-by":"crossref","first-page":"6500","DOI":"10.4049\/jimmunol.0901521","article-title":"Discrete domains of MARCH1 mediate its localization, functional interactions, and posttranscriptional control of expression","volume":"183","author":"Jabbour","year":"2009","journal-title":"J. Immunol."},{"key":"2025020609284073800_r40","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1002\/iid3.530","article-title":"Soluble CD127 potentiates IL-7 activity in vivo in healthy mice","volume":"9","author":"Aloufi","year":"2021","journal-title":"Immun. Inflamm. Dis."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/213\/10\/1467\/61754057\/ji2400253.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/213\/10\/1467\/61754057\/ji2400253.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T09:30:08Z","timestamp":1738834208000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/213\/10\/1467\/7960505"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,23]]},"references-count":40,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024,11,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.2400253","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,11]]},"published":{"date-parts":[[2024,9,23]]}}}