How a Cytokine Is Chaperoned through the Secretory Pathway by Complexing with Its Own Receptor: Lessons from Interleukin-15 (IL-15)/IL-15 Receptor α

While it is well appreciated that receptors for secreted cytokines transmit ligand-induced signals, little is known about additional roles for cytokine receptor components in the control of ligand transport and secretion. Here, we show that interleukin-15 (IL-15) translocation into the endoplasmic reticulum occurs independently of the presence of IL-15 receptor (cid:1) (IL-15R (cid:1) ). Subsequently, however, IL-15 is transported through the Golgi apparatus only in association with IL-15R (cid:1) and then is secreted. This intracellular IL-15/IL-15R (cid:1) complex already is formed in the endoplasmic reticulum and, thus, enables the further trafficking of complexed IL-15 through the secretory pathway. Just transfecting IL-15R (cid:1) in cells, which transcribe but normally do not secrete IL-15, suffices to induce IL-15 secretion. Thus, we provide the first evidence of how a cytokine is chaperoned through the secretory pathway by complexing with its own high-affinity the for the of secretion.

[1]  N. Reiling,et al.  Soluble interleukin (IL)-15Rα is generated by alternative splicing or proteolytic cleavage and forms functional complexes with IL-15. , 2011, The Journal of Biological Chemistry.

[2]  D. Kranz.  Faculty Opinions recommendation of Intracellular interaction of interleukin-15 with its receptor alpha during production leads to mutual stabilization and increased bioactivity. , 2008 .

[3]  A. Weissman,et al.  Ubiquitin ligases, critical mediators of endoplasmic reticulum-associated degradation. , 2007, Seminars in cell & developmental biology.

[4]  R. Paus,et al.  IL-15 constrains mast cell–dependent antibacterial defenses by suppressing chymase activities , 2007, Nature Medicine.

[5]  M. Verhage,et al.  Regulated exocytosis: merging ideas on fusing membranes. , 2007, Current opinion in cell biology.

[6]  J. Correale,et al.  Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death , 2007, Nature Immunology.

[7]  A. Diefenbach,et al.  Dendritic cells prime natural killer cells by trans-presenting interleukin 15. , 2007, Immunity.

[8]  S. High,et al.  ER Targeting Signals: More than Meets the Eye? , 2006, Cell.

[9]  T. Waldmann.  The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design , 2006, Nature Reviews Immunology.

[10]  R. Paus,et al.  IL-15/IL-15 receptor biology: a guided tour through an expanding universe. , 2006, Cytokine & growth factor reviews.

[11]  J. Sprent,et al.  Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[12]  M. Caligiuri,et al.  Human natural killer cell development and biology. , 2006, Blood reviews.

[13]  R. Paus,et al.  The interleukin‐15/interleukin‐15 receptor system as a model for juxtacrine and reverse signaling , 2006, BioEssays : news and reviews in molecular, cellular and developmental biology.

[14]  J. Grötzinger,et al.  The Structure of the Interleukin-15α Receptor and Its Implications for Ligand Binding* , 2006, Journal of Biological Chemistry.

[15]  Mark M Davis,et al.  T cells use two directionally distinct pathways for cytokine secretion , 2006, Nature Immunology.

[16]  A. Dvorak,et al.  Cytokine receptor-mediated trafficking of preformed IL-4 in eosinophils identifies an innate immune mechanism of cytokine secretion. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[17]  R. Paus,et al.  A promiscuous liaison between IL‐15 receptor and Axl receptor tyrosine kinase in cell death control , 2005, The EMBO journal.

[18]  J. Stow,et al.  A Role for the Phagosome in Cytokine Secretion , 2005, Science.

[19]  T. Yajima,et al.  A novel autoregulatory mechanism for transcriptional activation of the IL‐15 gene by a nonsecretable isoform of IL‐15 generated by alternative splicing , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  J. Dennis,et al.  N-Acetylglucosaminyltransferase V (Mgat5)-Mediated N-Glycosylation Negatively Regulates Th1 Cytokine Production by T Cells1 , 2004, The Journal of Immunology.

[21]  S. Sone,et al.  Synthesis and Secretion of Interleukin-15 by Freshly Isolated Human Bronchial Epithelial Cells , 2004, International Archives of Allergy and Immunology.

[22]  R. Silverman,et al.  Reverse Signaling through Membrane-bound Interleukin-15* , 2004, Journal of Biological Chemistry.

[23]  P. Burkett,et al.  Cutting Edge: Murine Dendritic Cells Require IL-15Rα to Prime NK Cells1 , 2004, The Journal of Immunology.

[24]  A. Plet,et al.  Natural, Proteolytic Release of a Soluble Form of Human IL-15 Receptor α-Chain That Behaves as a Specific, High Affinity IL-15 Antagonist1 , 2004, The Journal of Immunology.

[25]  I. Olsson,et al.  Hematopoietic secretory granules as vehicles for the local delivery of cytokines and soluble cytokine receptors at sites of inflammation. , 2004, European cytokine network.

[26]  S. Schwartzbach,et al.  Intracellular localization of the p35 subunit of murine IL-12. , 2003, Cytokine.

[27]  Barbara Imperiali,et al.  Oligosaccharyl transferase: gatekeeper to the secretory pathway. , 2002, Current opinion in chemical biology.

[28]  T. Waldmann,et al.  IL-15Rα Recycles and Presents IL-15 In trans to Neighboring Cells , 2002 .

[29]  J. Roth.  Protein N-glycosylation along the secretory pathway: relationship to organelle topography and function, protein quality control, and cell interactions. , 2002, Chemical reviews.

[30]  R. Paus,et al.  The IL-15Rα Chain Signals Through Association with Syk in Human B Cells1 , 2001, The Journal of Immunology.

[31]  M. Ernst,et al.  Mycobacteria-Induced TNF-α and IL-10 Formation by Human Macrophages Is Differentially Regulated at the Level of Mitogen-Activated Protein Kinase Activity1 , 2001, The Journal of Immunology.

[32]  A. Gaggero,et al.  IL-15/IL-15Rα intracellular trafficking in human melanoma cells and signal transduction through the IL-15Rα , 2000, Oncogene.

[33]  T. Waldmann,et al.  The Long Signal Peptide Isoform and Its Alternative Processing Direct the Intracellular Trafficking of Interleukin-15* , 2000, The Journal of Biological Chemistry.

[34]  K. Asadullah,et al.  Inhibition of Keratinocyte Apoptosis by IL-15: A New Parameter in the Pathogenesis of Psoriasis?1 , 2000, The Journal of Immunology.

[35]  P. Morrissey,et al.  Reversible Defects in Natural Killer and Memory Cd8 T Cell Lineages in Interleukin 15–Deficient Mice , 2000, The Journal of experimental medicine.

[36]  F. Magrangeas,et al.  Natural Splicing of Exon 2 of Human Interleukin-15 Receptor α-Chain mRNA Results in a Shortened Form with a Distinct Pattern of Expression* , 1999, The Journal of Biological Chemistry.

[37]  R. Paus,et al.  Death deflected: IL‐15 inhibits TNF‐α‐mediated apoptosis in fibroblasts by TRAF2 recruitment to the IL‐15Rα chain , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[38]  M. Zucca,et al.  Human monocytes constitutively express membrane-bound, biologically active, and interferon-gamma-upregulated interleukin-15. , 1999, Blood.

[39]  A. Gaggero,et al.  Differential intracellular trafficking, secretion and endosomal localization of two IL‐15 isoforms , 1999, European journal of immunology.

[40]  P. Revell,et al.  Interleukin 15 production by macrophages in the implant interface membrane of aseptically loosened joint replacements , 1998, Journal of materials science. Materials in medicine.

[41]  T. Dassopoulos,et al.  IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. , 1998, Immunity.

[42]  T. Waldmann,et al.  Generation of secretable and nonsecretable interleukin 15 isoforms through alternate usage of signal peptides. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[43]  R. Paus,et al.  Interleukin-15 protects from lethal apoptosis in vivo , 1997, Nature Medicine.

[44]  T. Pohl,et al.  Regulation of IL-15 secretion via the leader peptide of two IL-15 isoforms. , 1997, Journal of immunology.

[45]  M. Colombo,et al.  Identification of a novel interleukin-15 (IL-15) transcript isoform generated by alternative splicing in human small cell lung cancer cell lines. , 1996, Oncogene.

[46]  P. Scheurich,et al.  Both tumor necrosis factor receptors, TNFR60 and TNFR80, are involved in signaling endothelial tissue factor expression by juxtacrine tumor necrosis factor alpha. , 1995, Blood.

[47]  R. Dubose,et al.  Identification and cloning of a novel IL‐15 binding protein that is structurally related to the alpha chain of the IL‐2 receptor. , 1995, The EMBO journal.

[48]  D. Cosman,et al.  Utilization of the beta and gamma chains of the IL‐2 receptor by the novel cytokine IL‐15. , 1994, The EMBO journal.

[49]  T. Waldmann,et al.  The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[50]  V. Fung,et al.  Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. , 1994, Science.

[51]  J. Warrington,et al.  Assignment of genes encoding a unique cytokine (IL12) composed of two unrelated subunits to chromosomes 3 and 5. , 1992, Genomics.

[52]  T. Rapoport,et al.  The signal sequence receptor has a second subunit and is part of a translocation complex in the endoplasmic reticulum as probed by bifunctional reagents , 1990, The Journal of cell biology.

[53]  E. Hofsli,et al.  A flow cytometric and immunofluorescence microscopic study of tumor necrosis factor production and localization in human monocytes. , 1989, Cellular immunology.

[54]  Yu-Chung Yang,et al.  Human IL-3 (multi-CSF): Identification by expression cloning of a novel hematopoietic growth factor related to murine IL-3 , 1986, Cell.

[55]  W. Lindenmaier,et al.  Secretion of glycosylated human interleukin-2 by recombinant mammalian cell lines. , 1986, Carbohydrate research.

[56]  P. Stephens,et al.  Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity , 1985, Nature.

[57]  G. Blobel,et al.  Translocation of proteins across the endoplasmic reticulum III. Signal recognition protein (SRP) causes signal sequence-dependent and site- specific arrest of chain elongation that is released by microsomal membranes , 1981, The Journal of cell biology.

[58]  J. Rothman,et al.  Coated vesicles transport newly synthesized membrane glycoproteins from endoplasmic reticulum to plasma membrane in two successive stages. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[59]  S. Rose-John,et al.  Natural soluble interleukin-15Ralpha is generated by cleavage that involves the tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17). , 2004, The Journal of biological chemistry.

[60]  T. Waldmann,et al.  The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. , 1999, Annual review of immunology.

[61]  S. Sprang,et al.  Cytokine structural taxonomy and mechanisms of receptor engagement , 1993 .

[62]  R. Goodwin,et al.  Human interleukin 7: molecular cloning and growth factor activity on human and murine B-lineage cells. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[63]  R. Kelly,et al.  Constitutive and regulated secretion of proteins. , 1987, Annual review of cell biology.

[64]  H. Schachter.  Coordination between enzyme specificity and intracellular compartmentation in the control of protein‐bound oligosaccharide biosynthesis , 1984, Biology of the cell.