Eukaryotic translation initiation factor 5A, or eIF5A, is a small, abundant, and highly conserved protein found in nearly all eukaryotic life. The protein is encoded by two genes, EIF5A1 and EIF5A2, which produce two distinct isoforms. While the eIF5A1 isoform is present in almost all tissues, eIF5A2 expression is more restricted, primarily found in the brain and testes.
Although its name suggests a role in starting protein production, research has clarified that eIF5A is primarily involved in later stages of protein synthesis. Its main activities are promoting translation elongation, the process of assembling the protein chain, and assisting in translation termination. This function helps release the completed protein from the ribosome.
The Hypusination of eIF5A
For eIF5A to perform its functions, it must be activated through a unique post-translational modification called hypusination. This chemical alteration is exclusive to eIF5A and involves forming an unusual amino acid, hypusine, directly on the protein. This change is indispensable for its activity.
The creation of hypusine is a two-step enzymatic reaction that uses the polyamine spermidine as its sole building block. In the first step, the enzyme deoxyhypusine synthase (DHPS) transfers part of the spermidine molecule to an inactive eIF5A protein. This reaction forms an intermediate molecule known as deoxyhypusine-eIF5A.
Following this, a second enzyme, deoxyhypusine hydroxylase (DOHH), adds a hydroxyl group to the intermediate. This completes the conversion into the mature and fully functional hypusinated eIF5A. If either DHPS or DOHH does not function correctly, eIF5A cannot be activated, which has significant consequences for the cell.
Once activated, eIF5A interacts with ribosomes to resolve bottlenecks that occur during translation. The ribosome can stall when it encounters difficult-to-translate sequences in the messenger RNA (mRNA) blueprint, such as polyproline tracts. Activated eIF5A alleviates these stalls by interacting with the ribosome and transfer RNA (tRNA) to stabilize the complex, allowing protein synthesis to continue.
Cellular Regulation by eIF5A
By overcoming ribosomal stalling, eIF5A influences the production of a specific subset of proteins that contain challenging sequences. The functions of these target proteins span a wide spectrum of cellular activities, giving eIF5A a regulatory role in numerous processes.
One of the most direct outcomes of eIF5A function is its impact on cell proliferation. Because eIF5A facilitates the production of many proteins necessary for cell growth and division, its activity is closely linked to the cell’s ability to proliferate. This makes the eIF5A pathway particularly active in rapidly growing tissues and during development.
The protein also plays a role in apoptosis, or programmed cell death, which is a mechanism for eliminating damaged or unnecessary cells. eIF5A is involved in translating proteins that can trigger this process. This gives the protein a dual function, supporting cell growth while also participating in the machinery that can instruct a cell to die.
eIF5A activity is also connected to the proper functioning of the immune system. Immune cells must mount a rapid response to pathogens, which requires the swift production of signaling molecules and effector proteins. Hypusinated eIF5A has been shown to regulate the synthesis of specific transcription factors needed for a robust immune reaction, particularly in the activation of B cells and macrophages.
The Link Between eIF5A and Disease
When the activity of eIF5A is either too high or too low, it can disrupt cellular processes and lead to pathological conditions. In cancer, eIF5A is often hijacked by tumor cells to support their growth. Many types of cancer exhibit elevated levels of eIF5A and its hypusinating enzymes, helping them meet the high demand for protein synthesis required for rapid proliferation.
Conversely, impairments in the eIF5A hypusination pathway are investigated for their role in neurodegenerative disorders. In conditions like Alzheimer’s and Parkinson’s disease, the accumulation of toxic protein aggregates is a hallmark feature. Inefficient protein synthesis resulting from dysfunctional eIF5A may contribute to this by causing errors that lead to misfolded proteins. Rare neurodevelopmental disorders have also been associated with genetic variants in the genes for eIF5A and its modifying enzymes.
The eIF5A pathway is also exploited by viruses like HIV during infection. Viruses rely on the host cell’s machinery to produce viral proteins, many of which contain difficult-to-translate sequences. This dependency makes eIF5A a host factor that supports viral replication and can influence the progression of viral diseases.
eIF5A as a Therapeutic Target
The connection between eIF5A activity and disease has positioned it as a target for therapeutic intervention. Scientists are exploring strategies to modulate the eIF5A pathway, either by inhibiting its function where it is overactive or supporting it where its activity is diminished.
One therapeutic strategy focuses on inhibiting the eIF5A pathway for cancer treatment. Since many cancer cells are highly dependent on eIF5A for growth, blocking its activation could selectively harm them. Researchers are developing drugs that inhibit DHPS, the enzyme for the first step of hypusination, to cut off the supply of active eIF5A to cancer cells.
This approach has challenges, as eIF5A is also needed by healthy cells. However, the heightened reliance of cancer cells on this pathway may create a therapeutic window where they are more sensitive to its inhibition than normal tissues. This strategy aims to exploit a dependency of malignant cells while minimizing damage to the rest of the body.
An alternative therapeutic angle involves supporting eIF5A function, particularly in the context of aging. Cellular levels of spermidine, the substrate for hypusination, decline with age. This can lead to reduced eIF5A activation and may contribute to age-related declines in cellular function, including impaired immune responses.
Preliminary research suggests that dietary supplementation with spermidine, found in foods like aged cheese and whole grains, could help maintain the pathway’s activity. By providing more substrate for the hypusination reaction, spermidine supplementation could potentially support healthy aging by preserving the cell’s ability to synthesize proteins.