NDFIP1

Official Full Name

Nedd4 family interacting protein 1

Organism

Homo sapiens

GeneID

80762

Background

The protein encoded by this gene belongs to a small group of evolutionarily conserved proteins with three transmembrane domains. It is a potential target for ubiquitination by the Nedd4 family of proteins. This protein is thought to be part of a family of integral Golgi membrane proteins. [provided by RefSeq, Jul 2008]

Synonyms

N4WBP5;

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Detailed Information

Ndfip1 (Nedd4 family-interacting protein 1) is a versatile protein associated with the development of many diseases. Because of its specificity, it can be widely used in combination with Nedd4 (neural precursor cell expressed developmentally down-regulated protein 4) protein family. The Nedd4 protein family is an important E3 ubiquitin ligase in the body, and Ndfip1 functions in vivo by binding to Nedd4 and participating in the ubiquitination process. Current research has found that Ndfip1 has a positive effect on the survival of traumatic brain injury and cerebral ischemic neurons, and is also associated with certain autoimmune diseases and allergic diseases.

Structure and Distribution of Ndfip1

Ndfip1 is a conserved protein with 221 amino acid residues, two PY motifs at the N-terminus and three transmembrane hydrophobic domains at the C-terminus, suggesting that it has multiple potential functions. Ndfip1 interacts with members of the Nedd4 family. On the one hand, Ndfip1 can make Ndfip1 itself post-translationally modified. On the other hand, Ndfip1 can also regulate the E3 ubiquitin ligase activity and intracellular localization of Nedd4 family members, thereby indirectly regulating the modification and regulation effect on other target proteins by Nedd4 family members. Ndfip1 acts as an adaptor of the E3 ubiquitin ligase, which recruits substrate molecules to bind to E3 ubiquitin ligase and ubiquitinates the substrate to achieve ubiquitination specificity. Recent studies have found that Ndfip1 acts as a linker protein that expands the substrate protein range of Nedd4E3 ubiquitin ligase, especially those that lack the N-terminal PY motif, and binds to Nedd4 family proteins via Ndfip1 and is ubiquitinated. In addition, Ndfip1 can also act as an activator to release Nedd4E3 ubiquitin ligase from its self-inhibition.

Figure 1. NDFIP1 and NDFIP2. (Foot, N., et al. 2016)

Ndfip1 is widely expressed in various tissues and is highly expressed in adult liver, brain, kidney and heart. It is highly expressed in adult lung, testis, salivary gland, fetal tissue, etc., especially in adult brain, indicating Ndfip1 Has a wide range of effects, especially for the function of the brain. Low or no expression of Ndfip1 in leukemia cells, Burkitt lymphoma cells, colon cancer cells SW480 and A549 lung cancer cells suggests that Ndfip1 may not have a similar effect on tumor cells. Studies have shown that endogenous Ndfip1 is mainly localized on the Golgi apparatus, while the abnormal expression of Ndfip1 can destroy the structure of the Golgi apparatus. It can be seen that Ndfip1 is likely to be part of the Golgi membrane structure and has a certain influence on maintaining the stability and function of the Golgi matrix.

Neuroprotective Effects of Ndfip1

More and more evidence indicate that Ndfip1 is a neuroprotective protein. The Ndfip1/Nedd4 ubiquitination pathway is activated in traumatic brain injury and cerebral ischemic neuron survival, and is a powerful mechanism for increasing neuronal survival. Ndfip1 is essential for the development of neocortical pyramidal neuron dendrites and dendritic spines. Studies have found that selective knockout of Ndfip1 in embryonic mouse cerebral cortical pyramidal neurons leads to loss of control of neuronal growth, morphological complication and degenerate manifestations, including larger dents and shrinkage of the cell membrane. Selective knockout of Ndfip1 by postpartum mouse cerebral cortical pyramidal neurons resulted in a decrease in the number of neuronal dendrites and dendritic spines. Ndfip1 overexpression significantly attenuates MPP+ (1-methyl-4-phenylacridine)-induced apoptosis and plays an anti-apoptotic role. The proteasome inhibitor MG132 was able to reverse Ndfip1-mediated inhibition of DAT protein, suggesting that the ubiquitination-proteasome system is involved in this process.

References:

Foot, N. , & Kumar, S. . (2016). Ndfip1 and ndfip2.
Jia, W. , Xu, H. , Du, X. , Jiang, H. , & Xie, J. . (2015). Ndfip1 attenuated 6-ohda–induced iron accumulation via regulating the degradation of dmt1. Neurobiology of Aging, 36(2), 1183-1193.
Low, L. H., Chow, Y. L., Li, Y., Goh, C. P., Putz, U., & Silke, J., et al. (2015). Nedd4-family interacting protein 1 (ndfip1) is required for ubiquitination and nuclear trafficking of brca1-associated atm activator 1 (brat1) during the dna damage response. Journal of Biological Chemistry, 290(11), 7141-7150.

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