Transforming growth factor-beta-activated kinase 1 regulates natural killer cell-mediated cytotoxicity and cytokine...

Area of Science:

• Immunology
• Cell signaling

Background:

• Carma1 (caspase recruitment domain-containing membrane-associated guanylate kinase) is vital for NK cell signaling via Bcl10 and Malt1.
• Carma1 deficiency impairs NK cell cytotoxicity and cytokine production by reducing JNK1/2 phosphorylation and NF-κB activation.
• The downstream molecules linking Carma1 to NK cell effector functions remained undefined.

Purpose of the Study:

• To identify the downstream signaling molecules connecting Carma1 to NK cell effector functions.
• To elucidate the role of transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) in Carma1-mediated NK cell activation.

Main Methods:

• Investigated TAK1 presence and phosphorylation in NK cells.
• Assessed the impact of Carma1 deficiency on TAK1 phosphorylation.
• Utilized pharmacological TAK1 inhibitors and conditional in vivo TAK1 knockdown in mice.
• Analyzed NK cell-mediated cytotoxicity, cytokine/chemokine production, and signaling pathway activation (ERK1/2, JNK1/2, NF-κB, AP1).

Main Results:

• TAK1 is present in NK cells and activated via NKG2D, with its phosphorylation dependent on Carma1.
• Pharmacological inhibition or conditional knockdown of TAK1 significantly impaired NK cell cytotoxicity and production of IFN-γ, GM-CSF, MIP-1α, MIP-1β, and RANTES.
• TAK1 inhibition/knockdown blocked NKG2D-mediated phosphorylation of ERK1/2 and JNK1/2, and activation of NF-κB and AP1.

Conclusions:

• TAK1 acts as a critical downstream signaling molecule linking Carma1 to NK cell effector functions.
• TAK1 mediates NKG2D-induced NK cell cytotoxicity and cytokine/chemokine production through activation of JNK, ERK, NF-κB, and AP1 pathways.