The atypical PKCs in inflammation: NF-κB and beyond

Area of Science:

• Cellular Biology
• Immunology
• Molecular Signaling

Background:

• Protein Kinase C (PKC) isoforms have been implicated in nuclear factor-kappa B (NF-κB) pathway activation.
• Early research utilized pharmacological tools and pseudosubstrate inhibitors to explore PKC's role in NF-κB signaling.
• The PB1 network, involving PKC isoforms, plays a role in various cellular functions.

Purpose of the Study:

• To elucidate the complex interrelations within the PB1 network and their impact on cellular functions.
• To investigate the specific roles of PKC isoforms, particularly PKCζ, in NF-κB activation and regulation.
• To understand the involvement of these pathways in T-cell biology, bone homeostasis, metabolic syndrome, and cancer.

Main Methods:

• Analysis of genetic mouse knockout models.
• Pharmacological studies and pseudosubstrate inhibitor assays.
• Investigation of protein interactions within the PB1 network (p62, PKCζ, PKCλ/ι, NBR1).

Main Results:

• Genetic studies revealed the complexity and interrelations of the PB1 network components.
• PKCζ acts as a positive regulator of NF-κB via RelA but also suppresses inflammation by regulating interleukin-4 signaling.
• A complex of p62, PKCζ, PKCλ/ι, and NBR1 regulates T-cell effector responses through modulation of T-cell polarity.

Conclusions:

• PKC isoforms are critical regulators of NF-κB signaling with diverse roles.
• The PB1 network, particularly PKCζ, plays multifaceted roles in inflammation and immune responses.
• Further research is needed to fully understand the in vivo interplay of these pathways in diseases like obesity and cancer.