A PP4 holoenzyme balances physiological and oncogenic nuclear factor-kappa B signaling in T lymphocytes

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Signal transduction pathways, such as nuclear factor-kappa B (NF-κB), rely on kinase activity for activation.
• The termination of these signals, particularly through dephosphorylation, remains less understood.
• NF-κB signaling is crucial in T lymphocyte function and implicated in T cell lymphomas.

Purpose of the Study:

• To identify negative regulators of NF-κB signaling in T lymphocytes.
• To elucidate the mechanism of signal termination by dephosphorylation.
• To investigate the role of identified regulators in T cell lymphomas.

Main Methods:

• RNA interference (RNAi) screening in T lymphocytes.
• Co-immunoprecipitation to identify protein interactions.
• Analysis of T cell activation, proliferation, and signaling pathways.
• Investigation of NF-κB signaling in primary human T lymphocytes and T cell lymphomas.

Main Results:

• Protein phosphatase 4 regulatory subunit 1 (PP4R1) was identified as a negative regulator of NF-κB activity.
• PP4R1 functions within a PP4 holoenzyme, bridging the inhibitor of NF-κB kinase (IKK) complex and PP4c phosphatase.
• PP4R1 dephosphorylates and inactivates the IKK complex, thereby dampening NF-κB signaling.
• PP4R1 expression is induced upon T cell activation and proliferation.
• PP4R1 deficiency leads to sustained IKK activity, T cell hyperactivation, and aberrant NF-κB signaling.
• Downregulation of PP4R1 is associated with oncogenic NF-κB signaling in T cell lymphomas.

Conclusions:

• PP4R1 is a novel, activation-associated negative regulator of IKK activity in lymphocytes.
• PP4R1 plays a critical role in terminating NF-κB signaling by dephosphorylating the IKK complex.
• Loss of PP4R1 function contributes to T cell hyperactivation and promotes oncogenic NF-κB signaling in a subset of T cell lymphomas.