Nuclear factor-kappa B (NF-κB) is a protein complex found within nearly all animal cells, playing a central role in controlling how genes are expressed. This complex acts as a rapid responder to various cellular signals, influencing a wide array of biological processes. Its ability to turn specific genes on or off makes it a significant contributor to cellular function and response.
NF-κB: A Cellular Master Switch
NF-κB is not a single protein but rather a family of related proteins that assemble into various complexes, primarily functioning as “transcription factors.” A transcription factor is a protein that regulates gene activity by binding to specific DNA sequences, helping to turn genes “on” or “off.” In mammals, the NF-κB family includes five members: RelA (p65), RelB, c-Rel, NF-κB1 (p105/p50), and NF-κB2 (p100/p52). These proteins share a common region called the Rel homology domain, which enables them to bind DNA and form dimers.
In its inactive state, NF-κB complexes reside in the cytoplasm. They remain inactive because they are bound to inhibitory proteins known as IκB (Inhibitor of kappa B) proteins. IκB proteins mask the nuclear localization signals on NF-κB, preventing it from moving into the cell’s nucleus. This sequestration ensures that NF-κB is only activated when specific cellular conditions demand it.
Triggering the Switch: Activation Pathway
The activation of NF-κB begins when various external signals reach the cell. These signals can include inflammatory cues, bacterial or viral products, and different forms of cellular stress. Such stimuli trigger a cascade of events starting at the cell’s membrane. The key regulatory step in this process involves the activation of a protein complex called IκB kinase (IKK).
The IKK complex is composed of two catalytic subunits, IKKα and IKKβ, and a regulatory subunit known as NEMO (NF-κB essential modulator) or IKKγ. Upon receiving activating signals, IKK becomes phosphorylated and activated. This activated IKK then phosphorylates specific serine residues on the IκB protein. This phosphorylation acts as a tag, marking IκB for further processing.
Once phosphorylated, IκB undergoes ubiquitination, a process where small protein tags called ubiquitin are attached to it. This ubiquitination targets IκB for degradation by a cellular machinery called the proteasome. The proteasome breaks down the IκB protein, releasing NF-κB from its inhibitory bond. This release frees NF-κB, allowing it to become active and proceed to its next destination.
Journey to the Nucleus and Gene Ignition
Once NF-κB is released from IκB in the cytoplasm, it moves into the cell’s nucleus, a process known as nuclear translocation. The degradation of IκB unmasks the signals that allow NF-κB to enter the nucleus. This movement is important because the nucleus houses the cell’s genetic material, DNA.
Inside the nucleus, NF-κB binds to specific DNA sequences. These binding sites, often referred to as “κB sites” or “response elements,” are located near the genes that NF-κB controls. The binding of NF-κB to these sites initiates the process of gene transcription. This transcription involves creating messenger RNA (mRNA) copies from the DNA template.
The newly synthesized mRNA molecules then carry the genetic instructions out of the nucleus to the cell’s protein-making machinery. There, the mRNA is translated into new proteins. In this way, NF-κB directly “induces gene expression,” leading to the production of various proteins that carry out cellular functions. This sequence of events allows cells to respond to internal and external cues by altering their protein composition.
Impact on Health and Disease
NF-κB plays broad physiological roles in maintaining cellular balance. It is a central regulator of immune responses, enabling the body to fight off infections and respond to foreign invaders. The complex is also involved in inflammatory processes, helping to orchestrate the body’s protective reactions to injury or irritation. NF-κB contributes to cell survival, protecting cells from programmed cell death.
When NF-κB activity becomes dysregulated, it can contribute to various health problems. Persistent activation of NF-κB is observed in chronic inflammatory conditions, such as rheumatoid arthritis and inflammatory bowel disease, where its continued activity can drive ongoing inflammation.
NF-κB’s dysregulation is linked to certain cancers. In some tumor cells, NF-κB is constitutively active, meaning it is continuously “on,” which can promote cell proliferation and survival, contributing to disease progression. Understanding the intricate control of NF-κB offers potential avenues for developing therapies aimed at restoring balance in these conditions.