title: Secretion and biological activity of short signal peptide IL-15 is chaperoned by IL-15 receptor alpha in vivo.
abstract: The two known isoforms of IL-15 contain either a long signal peptide (LSP) or a short signal peptide (SSP), and are produced by alternatively spliced transcripts. It has been proposed that SSP IL-15 remains exclusively intracellular, and its function is unclear. In this study, we show that, similar to LSP IL-15, the SSP IL-15 is stabilized and secreted efficiently upon coexpression of IL-15Ralpha. Coinjection of SSP IL-15- and IL-15Ralpha-expressing plasmids into mice resulted in increased plasma levels of bioactive heterodimeric IL-15 and mobilization and expansion of NK and T cells. Therefore, SSP IL-15 is secreted and bioactive when produced as a heterodimer with IL-15Ralpha in the same cell. The apparent t(1/2) of this heterodimer is lower compared with LSP IL-15/IL-15Ralpha, due to different intracellular processing. Coexpression of both LSP IL-15 and SSP IL-15 in the presence of IL-15Ralpha results in lower levels of bioactive IL-15, indicating that LSP and SSP IL-15 compete for the binding to IL-15Ralpha when expressed in the same cell. Because the SSP IL-15 interaction to IL-15Ralpha leads to a complex with lower apparent stability, SSP IL-15 functions as competitive inhibitor of LSP IL-15. The data suggest that usage of alternative splicing is an additional level of control of IL-15 activity. Expression of both SSP and LSP forms of IL-15 appears to be conserved in many mammals, suggesting that SSP may be important for expressing a form of IL-15 with lower magnitude or duration of biological effects.
authors.affiliation: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bergamaschi
authors.forename: Rashmi
authors.initials: R
authors.lastname: Jalah
authors.forename: Viraj
authors.initials: V
authors.lastname: Kulkarni
authors.forename: Margherita
authors.initials: M
authors.lastname: Rosati
authors.forename: Gen-Mu
authors.initials: GM
authors.lastname: Zhang
authors.forename: Candido
authors.initials: C
authors.lastname: Alicea
authors.forename: Andrei S
authors.initials: AS
authors.lastname: Zolotukhin
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Felber
authors.forename: George N
authors.initials: GN
authors.lastname: Pavlakis
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism*; D053720:Interleukin-15 Receptor alpha Subunit / Q000378:metabolism*; D007424:Intracellular Fluid / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018832:Molecular Chaperones / Q000378:metabolism*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D021382:Protein Sorting Signals; D055550:Protein Stability; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection
chemical_list: D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D018832:Molecular Chaperones; D010446:Peptide Fragments; D020033:Protein Isoforms; D021382:Protein Sorting Signals; D012333:RNA, Messenger
references.citation: J Immunol. 2006 Nov 1;177(9):6072-80
references.pmid: 17056533
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9166-71
references.pmid: 16757567
references.citation: Immunity. 2002 Nov;17(5):537-47
references.pmid: 12433361
references.citation: Mol Cell Biol. 2008 Aug;28(15):4851-61
references.pmid: 18505820
references.citation: J Biol Chem. 2008 Feb 15;283(7):4189-99
references.pmid: 18055460
references.citation: J Immunol. 2004 Dec 1;173(11):6537-41
references.pmid: 15557143
references.citation: Nat Med. 2007 Aug;13(8):927-34
references.pmid: 17643110
references.citation: J Immunol. 2008 Feb 15;180(4):2099-106
references.pmid: 18250415
references.citation: Eur J Immunol. 1999 Apr;29(4):1265-74
references.pmid: 10229094
references.citation: J Immunol. 2005 Jul 1;175(1):112-23
references.pmid: 15972637
references.citation: J Immunol. 1998 May 1;160(9):4418-26
references.pmid: 9574546
references.citation: J Exp Med. 2001 Oct 15;194(8):1187-94
references.pmid: 11602647
references.citation: J Biol Chem. 2002 Feb 8;277(6):3935-42
references.pmid: 11724776
references.citation: Virology. 1995 Nov 10;213(2):439-49
references.pmid: 7491768
references.citation: J Exp Med. 2003 Apr 21;197(8):977-84
references.pmid: 12695489
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14444-9
references.pmid: 9405632
references.citation: J Immunol. 2003 May 15;170(10):5045-55
references.pmid: 12734349
references.citation: Blood. 2004 Feb 1;103(3):988-94
references.pmid: 14512307
references.citation: Blood. 1997 Jan 1;89(1):201-11
references.pmid: 8978293
references.citation: Immunity. 1996 Apr;4(4):329-36
references.pmid: 8612127
references.citation: J Immunol. 1998 Jan 15;160(2):936-42
references.pmid: 9551932
references.citation: J Exp Med. 2008 May 12;205(5):1213-25
references.pmid: 18458113
references.citation: J Virol. 1994 Dec;68(12):7944-52
references.pmid: 7966585
references.citation: Gene Ther. 1999 Jul;6(7):1258-66
references.pmid: 10455434
references.citation: J Virol. 2005 Jul;79(13):8480-92
references.pmid: 15956591
references.citation: J Exp Med. 2000 Jan 3;191(1):157-70
references.pmid: 10620614
references.citation: J Exp Med. 2004 Oct 4;200(7):825-34
references.pmid: 15452177
references.citation: J Biol Chem. 2006 Jan 20;281(3):1612-9
references.pmid: 16284400
references.citation: Oncogene. 1996 May 16;12(10):2187-92
references.pmid: 8668345
references.citation: Blood. 2005 Oct 1;106(7):2302-10
references.pmid: 15976182
references.citation: DNA Cell Biol. 2007 Dec;26(12):827-40
references.pmid: 17979522
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2897-902
references.pmid: 8610139
references.citation: FASEB J. 2005 Jan;19(1):19-28
references.pmid: 15629891
references.citation: Biochem Biophys Res Commun. 2001 Dec 21;289(5):1088-92
references.pmid: 11741303
references.citation: J Biol Chem. 2000 Sep 29;275(39):30653-9
references.pmid: 10869346
references.citation: J Immunol. 1997 Jan 1;158(1):255-62
references.pmid: 8977197
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4724-9
references.pmid: 12671073
references.citation: Eur J Immunol. 1997 May;27(5):1049-54
references.pmid: 9174591
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5616-21
references.pmid: 15060278
references.citation: J Immunol. 2005 Jul 15;175(2):693-9
references.pmid: 16002664
references.citation: J Virol. 1997 Jul;71(7):4892-903
references.pmid: 9188551
references.citation: J Biol Chem. 2007 May 4;282(18):13167-79
references.pmid: 17327231