title: Transforming growth factor-beta-activated kinase 1 regulates natural killer cell-mediated cytotoxicity and cytokine production.
abstract: Carma1, a caspase recruitment domain-containing membrane-associated guanylate kinase, initiates a unique signaling cascade via Bcl10 and Malt1 in NK cells. Carma1 deficiency results in reduced phosphorylation of JNK1/2 and activation of NF-κB that lead to impaired NK cell-mediated cytotoxicity and cytokine production. However, the precise identities of the downstream signaling molecules that link Carma1 to these effector functions were not defined. Here we show that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is abundantly present in NK cells, and activation via NKG2D results in its phosphorylation. Lack of Carma1 considerably reduced TAK1 phosphorylation, demonstrating the dependence of TAK1 on Carma1 in NKG2D-mediated NK cell activations. Pharmacological inhibitor to TAK1 significantly reduced NK-mediated cytotoxicity and its potential to generate IFN-γ, GM-CSF, MIP-1α, MIP-1β, and RANTES. Conditional in vivo knockdown of TAK1 in NK cells from Mx1Cre(+)TAK1(fx/fx) mice resulted in impaired NKG2D-mediated cytotoxicity and cytokine/chemokine production. Inhibition or conditional knockdown of TAK1 severely impaired the NKG2D-mediated phosphorylation of ERK1/2 and JNK1/2 and activation of NF-κB and AP1. Our results show that TAK1 links Carma1 to NK cell-mediated effector functions.
authors.affiliation: Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: Kamalakannan
authors.initials: K
authors.lastname: Rajasekaran
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chu
authors.forename: Pawan
authors.initials: P
authors.lastname: Kumar
authors.forename: Yechen
authors.initials: Y
authors.lastname: Xiao
authors.forename: Mathew
authors.initials: M
authors.lastname: Tinguely
authors.forename: Asanga
authors.initials: A
authors.lastname: Samarakoon
authors.forename: Tae Whan
authors.initials: TW
authors.lastname: Kim
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.forename: Monica S
authors.initials: MS
authors.lastname: Thakar
authors.forename: Jiwang
authors.initials: J
authors.lastname: Zhang
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Malarkannan
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D007694:Killer Cells, Natural / Q000276:immunology*; D020930:MAP Kinase Kinase Kinases / Q000276:immunology*; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D020930:MAP Kinase Kinase Kinases; D000099151:MAP Kinase Kinase Kinase 7; C496467:Card11 protein, mouse