Interleukin-15 enhances proteasomal degradation of bid in normal lymphocytes: implications for large granular lymphocyte leukemias.
Large granular lymphocyte (LGL) leukemia is a clonal proliferative disease of T and natural killer (NK) cells. Interleukin (IL)-15 is important for the development and progression of LGL leukemia and is a survival factor for normal NK and T memory cells. IL-15 alters expression of Bcl-2 family members, Bcl-2, Bcl-XL, Bim, Noxa, and Mcl-1; however, effects on Bid have not been shown. Using an adoptive transfer model, we show that NK cells from Bid-deficient mice survive longer than cells from wild-type control mice when transferred into IL-15-null mice. In normal human NK cells, IL-15 significantly reduces Bid accumulation. Decreases in Bid are not due to alterations in RNA accumulation but result from increased proteasomal degradation. IL-15 up-regulates the E3 ligase HDM2 and we find that HDM2 directly interacts with Bid. HDM2 suppression by short hairpin RNA increases Bid accumulation lending further support for HDM2 involvement in Bid degradation. In primary leukemic LGLs, Bid levels are low but are reversed with bortezomib treatment with subsequent increases in LGL apoptosis. Overall, these data provide a novel molecular mechanism for IL-15 control of Bid that potentially links this cytokine to leukemogenesis through targeted proteasome degradation of Bid and offers the possibility that proteasome inhibitors may aid in the treatment of LGL leukemia.
Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, and SAIC Frederick, Frederick, Maryland 21702-1201, USA.
Deborah L
DL
Hodge
Jun
J
Yang
Matthew D
MD
Buschman
Paul M
PM
Schaughency
Hong
H
Dang
William
W
Bere
Yili
Y
Yang
Ram
R
Savan
Jeff J
JJ
Subleski
Xiao-Ming
XM
Yin
Thomas P
TP
Loughran
Howard A
HA
Young
D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein / Q000096:biosynthesis / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D019409:Interleukin-15 / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D054066:Leukemia, Large Granular Lymphocytic / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D008214:Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D051736:Proto-Oncogene Proteins c-mdm2 / Q000276:immunology / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D019409:Interleukin-15; D007376:Interleukin-2; D061988:Proteasome Inhibitors; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex