Glucocorticoids downregulate Fyn and inhibit IP(3)-mediated calcium signaling to promote autophagy in T lymphocytes.
T cell receptor activation induces inositol 1,4,5 trisphosphate (IP(3))-mediated calcium signaling that is essential for cell metabolism and survival. Moreover, inhibitors of IP(3) or pharmacological agents that disrupt calcium homeostasis readily induce autophagy. Using a glucocorticoid-sensitive CD4/CD8 positive T cell line, we found that dexamethasone prevented both IP(3)-mediated and spontaneous calcium signals within a timeframe that correlated with the induction of autophagy. We determined that this loss in IP(3)-mediated calcium signaling was dependent upon the downregulation of the Src kinase Fyn at the mRNA and protein level. Because it has previously been shown that Fyn positively regulates IP(3)-mediated calcium release by phosphorylating Type I IP(3) receptors (IP(3)R1), we investigated the effect of glucocorticoids on IP(3)R1 phosphorylation at Tyr353. Accordingly, glucocorticoid-mediated downregulation of Fyn prevented IP(3)R1 phosphorylation at Tyr353. Moreover, selective knockdown of Fyn or treatment with a Src inhibitor also attenuated IP(3)-mediated calcium release and induced autophagy. Collectively, these data indicate that glucocorticoids promote autophagy by inhibiting IP(3)-dependent calcium signals. These findings carry important therapeutic implications given the widespread use of dexamethasone as both a chemotherapeutic and immunosuppressive agent.
Harr
Michael W
MW
Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
McColl
Karen S
KS
Zhong
Fei
F
Molitoris
Jason K
JK
Distelhorst
Clark W
CW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects*; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D005938:Glucocorticoids; D053496:Inositol 1,4,5-Trisphosphate Receptors; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D003907:Dexamethasone; D015544:Inositol 1,4,5-Trisphosphate; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn
Am J Physiol. 1997 Apr;272(4 Pt 1):C1241-9
9142849
Cell Death Differ. 2009 Jul;16(7):1006-17
19325567
Biochem J. 2003 Apr 1;371(Pt 1):15-27
12485116
J Biol Chem. 2004 Apr 16;279(16):16311-6
14761954
Proc Natl Acad Sci U S A. 1977 Feb;74(2):638-42
322136
N Engl J Med. 2005 Oct 20;353(16):1711-23
16236742
Autophagy. 2008 Jul;4(5):612-20
18362516
J Immunol. 1984 Jan;132(1):38-42
6317746
Cell Mol Life Sci. 2006 Jan;63(1):60-72
16314919
Cell. 1994 Jan 28;76(2):263-74
8293463
Blood. 2008 Feb 15;111(4):2269-79
18056483
Adv Exp Med Biol. 1999;457:607-14
10500840
Mol Endocrinol. 1993 May;7(5):686-93
8316252
Autophagy. 2006 Apr-Jun;2(2):132-4
16874097
Genes Cancer. 2010 Jan;1(1):40-9
20811583
J Biol Chem. 1992 Dec 25;267(36):25864-72
1464601
Immunity. 2001 Oct;15(4):497-502
11672532
J Biol Chem. 2009 Nov 13;284(46):31860-71
19776014
Science. 1996 Jun 7;272(5267):1492-4
8633244
J Exp Med. 2007 Jan 22;204(1):25-31
17190837
Oncogene. 2008 Oct 27;27(50):6407-18
18955969
Arch Biochem Biophys. 1989 Feb 15;269(1):365-70
2537063
J Exp Med. 2001 Apr 2;193(7):803-14
11283153
Nat Immunol. 2006 Jan;7(1):25-32
16357855
J Cell Biol. 2005 Sep 26;170(7):1101-11
16186256
J Exp Med. 1992 Mar 1;175(3):637-46
1740658
Oncogene. 2006 Mar 23;25(13):1903-13
16301999
Autophagy. 2008 Feb;4(2):151-75
18188003
Cell Death Differ. 2004 Jul;11 Suppl 1:S45-55
15243581
Curr Biol. 2004 Nov 9;14(21):R933-5
15530388
Nat Chem Biol. 2008 May;4(5):295-305
18391949
J Biol Chem. 1985 Mar 25;260(6):3440-50
3838314
Cell Death Differ. 2002 Jan;9(1):6-19
11803370
Cell. 2010 Feb 5;140(3):313-26
20144757
J Biol Chem. 2004 Dec 17;279(51):52850-9
15485889
Cell Death Differ. 2010 Sep;17(9):1381-91
20300113
Curr Opin Immunol. 2003 Jun;15(3):299-307
12787755
J Biol Chem. 2003 Jul 18;278(29):27053-8
12736248
J Biol Chem. 2003 Jun 27;278(26):23861-7
12676946
J Cell Biol. 2007 Dec 3;179(5):923-34
18056410
Oncogene. 2004 Oct 18;23(48):7990-8000
15489916
J Biol Chem. 2008 Apr 18;283(16):10357-65
18272518
J Immunol. 1996 Jun 15;156(12):4555-61
8648096
Annu Rev Immunol. 2001;19:497-521
11244045
Cell Death Differ. 2007 May;14(5):1029-39
17256008
Cell Death Differ. 2009 Jul;16(7):1018-29
19390558
Mol Cell. 2007 Jan 26;25(2):193-205
17244528
J Exp Med. 1992 May 1;175(5):1235-45
1569395
Oncogene. 2003 Nov 24;22(53):8619-27
14634623
J Clin Invest. 2009 May;119(5):1109-23
19363292
Blood. 2005 Sep 1;106(5):1703-10
15899916
J Biol Chem. 2006 Dec 22;281(51):39128-34
17074751
EMBO Rep. 2006 Oct;7(10):1023-9
16888650
Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):808-16
18573473
Nat Rev Immunol. 2005 Nov;5(11):844-52
16239903
Mol Cancer Ther. 2009 Feb;8(2):394-406
19190119
Autophagy. 2007 Jul-Aug;3(4):381-3
17457036
Annu Rev Immunol. 2000;18:309-45
10837061
J Clin Invest. 1993 Apr;91(4):1481-9
8473495
Am J Physiol Endocrinol Metab. 2000 Jul;279(1):E74-82
10893325
Adv Exp Med Biol. 1991;283:419-25
1648868