TY - JOUR
T1 - Phosphorylation of the CARMA1 linker controls NF-κB activation
AU - Sommer, Karen
AU - Guo, Beichu
AU - Pomerantz, Joel L.
AU - Bandaranayake, Ashok D.
AU - Moreno-García, Miguel E.
AU - Ovechkina, Yulia L.
AU - Rawlings, David J.
N1 - Funding Information:
We thank the following individuals for kindly providing reagents: Drs. Margot Thome, Edward Clark, Steve Ziegler, Tucker LeBien, and Donald Thornton. We also would like to thank members of the Rawlings lab for technical assistance and thoughtful discussions. B.G. and A.D.B. were partially supported by a CRI Immunology Training Grant. During the course of this work, J.L.P. was a Special Fellow of the Leukemia and Lymphoma Society. D.J.R. is the recipient of a McDonnell Scholar Award and a Leukemia and Lymphoma Society Scholar Award. This work was supported, in part, by NIH grants HD37091, CA81140, and HL075453 and by the American Cancer Society.
PY - 2005/12
Y1 - 2005/12
N2 - PKC isoforms and CARMA1 play crucial roles in immunoreceptor-dependent NF-κB activation. We tested whether PKC-dependent phosphorylation of CARMA1 directly regulates this signaling cascade. B cell antigen receptor (BCR) engagement led to the progressive recruitment of CARMA1 into lipid rafts and to the association of CARMA1 with, and phosphorylation by, PKCβ. Furthermore, PKCβ interacted with the serine-rich CARMA1 linker, and both PKCβ and PKCθ phosphorylated identical serine residues (S564, S649, and S657) within this linker. Mutation of two of these sites ablated the functional activity of CARMA1. In contrast, deletion of the linker resulted in constitutive, receptor- and PKC-independent NF-κB activation. Together, our data support a model whereby CARMA1 phosphorylation controls NF-κB activation by triggering a shift from an inactive to an active CARMA1 conformer. This PKC-dependent switch regulates accessibility of the CARD and CC domains and controls assembly and full activation of the membrane-associated IκB kinase (IKK) signalosome.
AB - PKC isoforms and CARMA1 play crucial roles in immunoreceptor-dependent NF-κB activation. We tested whether PKC-dependent phosphorylation of CARMA1 directly regulates this signaling cascade. B cell antigen receptor (BCR) engagement led to the progressive recruitment of CARMA1 into lipid rafts and to the association of CARMA1 with, and phosphorylation by, PKCβ. Furthermore, PKCβ interacted with the serine-rich CARMA1 linker, and both PKCβ and PKCθ phosphorylated identical serine residues (S564, S649, and S657) within this linker. Mutation of two of these sites ablated the functional activity of CARMA1. In contrast, deletion of the linker resulted in constitutive, receptor- and PKC-independent NF-κB activation. Together, our data support a model whereby CARMA1 phosphorylation controls NF-κB activation by triggering a shift from an inactive to an active CARMA1 conformer. This PKC-dependent switch regulates accessibility of the CARD and CC domains and controls assembly and full activation of the membrane-associated IκB kinase (IKK) signalosome.
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U2 - 10.1016/j.immuni.2005.09.014
DO - 10.1016/j.immuni.2005.09.014
M3 - Article
C2 - 16356855
AN - SCOPUS:28844500398
SN - 1074-7613
VL - 23
SP - 561
EP - 574
JO - Immunity
JF - Immunity
IS - 6
ER -