IκBα is one of the most important members of the IκB protein family — which are inhibitors of the NF-κB pathway, a key regulatory system in inflammation, immunity, and cell survival.
🧬 What Is IκBα?
- It is a specific isoform of the IκB proteins.
- Its primary job is to bind NF-κB in the cytoplasm and prevent it from entering the nucleus, thus keeping it inactive under normal conditions.
- It acts as a “gatekeeper” for the inflammatory response.
🔄 How IκBα Functions in the NF-κB Pathway:
- In the resting state, IκBα binds tightly to NF-κB (usually the p65/p50 dimer), masking its nuclear localization signal.
- When a cell receives a signal (like stress, infection, cytokines), the IKK complex phosphorylates IκBα at specific serine residues (Ser32 and Ser36).
- Phosphorylated IκBα is ubiquitinated and degraded by the proteasome.
- This frees NF-κB, allowing it to translocate to the nucleus and activate target genes involved in inflammation, immunity, and survival.
- Among those target genes is IκBα itself — creating a negative feedback loop. New IκBα is produced to re-bind and shut down NF-κB, helping prevent overactivation.
🔁 Negative Feedback Loop:
NF-κB → turns on IκBα → IκBα turns off NF-κB
This feedback mechanism ensures that inflammation is tightly controlled and doesn’t become chronic or damaging.
⚠️ Why IκBα Matters:
- Too little IκBα → unchecked inflammation (seen in chronic disease or cancer)
- Too much IκBα → impaired immune response (immune suppression)
- Target for drugs: Modulating IκBα levels is being studied in cancer, autoimmune disorders, and neuroinflammation.
🧠 In Summary:
IκBα is a critical protein that keeps NF-κB “off” until it’s needed. When the body is exposed to stress or infection, IκBα is destroyed, allowing NF-κB to activate survival and inflammation genes — but then IκBα is rebuilt to turn the system back off. It’s a master regulator of controlled inflammation.