Phosphatidylinositol-3 phosphatase myotubularin-related protein 6 negatively regulates CD4 T cells.
Intracellular Ca2+ levels rapidly rise following cross-linking of the T-cell receptor (TCR) and function as a critical intracellular second messenger in T-cell activation. It has been relatively under appreciated that K+ channels play an important role in Ca2+ influx into T lymphocytes by helping to maintain a negative membrane potential which provides an electrochemical gradient to drive Ca2+ influx. Here we show that the Ca2+-activated K+ channel, KCa3.1, which is critical for Ca2+ influx in reactivated naive T cells and central memory T cells, requires phosphatidylinositol-3 phosphatase [PI(3)P] for activation and is inhibited by the PI(3)P phosphatase myotubularin-related protein 6 (MTMR6). Moreover, by inhibiting KCa3.1, MTMR6 functions as a negative regulator of Ca2+ influx and proliferation of reactivated human CD4 T cells. These findings point to a new and unexpected role for PI(3)P and the PI(3)P phosphatase MTMR6 in the regulation of Ca2+ influx in activated CD4 T cells and suggest that MTMR6 plays a critical role in setting a minimum threshold for a stimulus to activate a T cell.
Srivastava
Shekhar
S
Department of Pharmacology, The Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
Ko
Kyung
K
Choudhury
Papiya
P
Li
Zhai
Z
Johnson
Amanda K
AK
Nadkarni
Vivek
V
Unutmaz
Derya
D
Coetzee
William A
WA
Skolnik
Edward Y
EY
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D018408:Patch-Clamp Techniques; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism
D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D010744:Phosphoric Monoester Hydrolases; C513490:MTMR6 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C061816:phosphatidylinositol-3-phosphatase; D002118:Calcium