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B p65 Serine 536 Phosphorylation Induced by T Cell Costimulation Is Mediated by IB Kinase 
and Controls the Kinetics of p65 Nuclear Import 1
,
* University of Bern, Department of Chemistry and Biochemistry, Bern, Switzerland;
Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan;
PRESTO, JST, Saitama, Japan;
Subteam for BioResponse Integration, RIKEN (Institute of Physical and Chemical Research), BioResource Center, Tsukuba, Ibaraki, Japan; and
¶ Institute of Pharmacology, Medical School Hannover, Hannover, Germany
Full transcriptional activity of the nuclear, DNA-bound form of NF-
B requires additional posttranslational modifications. In this study, we systematically mapped the T cell costimulation-induced phosphorylation sites within the C-terminal half of the strongly trans-activating NF-B p65 subunit and identified serine 536 as the main phosphorylation site. The transient kinetics of serine 536 phosphorylation paralleled the kinetics of IB
and IB kinase (IKK) phosphorylation and also mirrored the principle of T cell costimulation. The TCR-induced pathway leading to serine 536 phosphorylation is regulated by the kinases Cot (Tpl2), receptor interacting protein, protein kinase C
, and NF-B-inducing kinase, but is independent from the phosphatidylinositol 3-kinase/Akt signaling pathway. Loss-of-function and gain-of-function experiments showed phosphorylation of p65 serine 536 by IKK
, but not by IKK. Phosphorylation occurs within the cytoplasmic and intact NF-B/IB complex and requires prior phosphorylation of IB at serines 32 and 36. Reconstitution of p65–/– cells either with wild-type p65 or a p65 mutant containing a serine to alanine mutation revealed the importance of this phosphorylation site for cytosolic IB localization and the kinetics of p65 nuclear import.
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