Suppressor of cytokine signaling 2 regulates IL-15-primed human NK cell function via control of phosphorylated Pyk2.
NK cells are capable of killing virus-infected or tumor cells and producing IFN-gamma. Resting NK cells, however, have only minimal cytolytic activity and secrete a low level of IFN-gamma. The cytokine IL-15 can promote the expression of effector functions by resting NK cells. In this study, we demonstrate that suppressor of cytokine signaling 2 (SOCS2) has a novel role in IL-15-primed human NK cell function. SOCS2 expression was upregulated in NK cells following stimulation with IL-15. During IL-15-mediated NK cell priming, SOCS2 interacted with phosphorylated proline-rich tyrosine kinase 2 (Pyk2) at tyrosine 402 (p-Pyk2(Tyr402)) and induced the proteasome-mediated degradation of p-Pyk2(Tyr402) via ubiquitination. Knockdown of SOCS2 resulted in the accumulation of p-Pyk2(Tyr402) and blocked NK cell effector functions. In addition, NK cell cytolytic activity and IFN-gamma production were inhibited by overexpression of the wild-type of Pyk2 but not by the overexpression of tyrosine 402 mutant of Pyk2. These results suggest that SOCS2 regulates human NK cell effector functions via control of phosphorylated Pyk2 depending on IL-15 existence.
Lee
Suk Hyung
SH
Cell Therapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Yun
Sohyun
S
Piao
Zheng-Hao
ZH
Jeong
Mira
M
Kim
Dong Oh
DO
Jung
Haiyoung
H
Lee
Jiwon
J
Kim
Mi Jeong
MJ
Kim
Mi Sun
MS
Chung
Jin Woong
JW
Kim
Tae-Don
TD
Yoon
Suk Ran
SR
Greenberg
Philip D
PD
Choi
Inpyo
I
D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000494:pharmacology*; D019169:Jurkat Cells; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D034622:RNA Interference; D053647:Receptors, Interleukin-15 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D019409:Interleukin-15; D053647:Receptors, Interleukin-15; C106643:SOCS2 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine; D007371:Interferon-gamma; D051418:Focal Adhesion Kinase 2