Phosphorylation Of Cullin3 By The Pseudokinase Aldh18A1 Disrupts Keap1-Mediated Nrf2 Degradation
Our bodies have a vital defense mechanism against cellular damage, often triggered by environmental stressors or the aging process. A key player in this defense is a protein called NRF2, which acts as a master switch to activate protective genes. Under normal conditions, the levels of NRF2 are carefully controlled by a cellular “cleanup crew” that includes a protein called KEAP1 and a larger complex containing Cullin3. This crew works by tagging NRF2 for destruction, ensuring that our protective systems are only activated when truly necessary.
However, new research has uncovered a fascinating way this regulatory process can be influenced. Scientists have discovered that a protein known as ALDH18A1, which belongs to a class called “pseudokinases” (proteins that resemble enzymes that add phosphate groups to other molecules), can directly modify Cullin3 by attaching a phosphate group to it. This modification acts like a disruption to the normal function of the cleanup crew, making it less efficient at tagging NRF2 for degradation.
When NRF2 is not broken down as quickly, its levels increase, allowing it to activate a wider range of genes that protect our cells from various forms of stress. This discovery provides a novel insight into how our body’s antioxidant and protective responses are regulated, potentially opening new avenues for understanding and addressing diseases associated with cellular damage and oxidative stress.
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