NEDD4L
Description
The NEDD4L (NEDD4 like E3 ubiquitin protein ligase) is a protein-coding gene located on chromosome 18.
NEDD4L (Neural precursor cell expressed developmentally downregulated gene 4-like) is an enzyme (ubiquitin ligase) belonging to the NEDD4 family. It is involved in regulating various cellular processes, including signaling pathways, protein degradation, and ion channel activity. The protein is encoded by the NEDD4L gene in humans (NEDD4-2 in mice). NEDD4L is involved in the ubiquitination (tagging) of target proteins, leading to their downregulation or degradation. For example, NEDD4L regulates the epithelial sodium channel (ENaC) in the kidneys, influencing salt balance. In Liddle's Syndrome, NEDD4L's ability to bind to ENaC is impaired, leading to salt retention and hypertension. NEDD4L is widely expressed in various tissues and plays a crucial role in many cellular functions.
NEDD4L is an E3 ubiquitin ligase that attaches ubiquitin molecules to target proteins, thereby controlling their function and fate within the cell. This process, known as ubiquitination, is critical for regulating numerous cellular pathways, including:
- Autophagy: NEDD4L plays a role in the breakdown and recycling of cellular components, potentially contributing to the regulation of cellular growth.
- Innate Immunity: NEDD4L is involved in the body's first line of defense against infections, helping to control the activity of signaling molecules involved in immune responses.
- DNA Repair: NEDD4L contributes to the repair of damaged DNA, ensuring the stability of the genome.
NEDD4L also exerts influence over specific signaling pathways:
- TGF-beta Signaling: By tagging the signaling molecules SMAD2 and TGFBR1 for degradation, NEDD4L inhibits the activity of the TGF-beta pathway, which plays a crucial role in cellular growth, development, and immune responses.
- TOR Signaling: NEDD4L is implicated in the regulation of TOR signaling, a pathway that controls cell growth and metabolism.
Furthermore, NEDD4L has a role in the ubiquitination and internalization (removal from the cell surface) of various membrane proteins, including ion channels:
- Sodium Channels (ENaC, SCN2A, SCN3A, SCN5A, SCN9A, SCN10A): NEDD4L regulates the activity of these channels, which are involved in the transmission of nerve impulses and the control of muscle contraction.
- Potassium Channels (KCNA3, KCNH2, KCNQ2, KCNQ3): NEDD4L influences the function of potassium channels, which are essential for maintaining the electrical balance of cells and regulating nerve impulses.
- Chloride Channels (CLC5): NEDD4L regulates the flow of chloride ions, which are critical for various physiological processes, including nerve impulse transmission and fluid balance.
Other notable actions of NEDD4L include:
- Ubiquitination of BRAT1: This protein plays a role in cell growth, and its ubiquitination by NEDD4L is enhanced by the protein NDFIP1.
- Dendrite Formation: NEDD4L contributes to the growth and development of dendrites, the branched extensions of nerve cells.
- NGF Signaling: NEDD4L regulates the levels of NTRK1, a receptor involved in the NGF (nerve growth factor) signaling pathway, which is crucial for the development and survival of neurons.
- Antiviral Immunity: NEDD4L is involved in antiviral responses by controlling the ubiquitination of TRAF3, a protein crucial for the signaling pathways of various antiviral cytokines.
- Ubiquitination of TTYH2 and TTYH3: These proteins are involved in the regulation of ion channels, and NEDD4L controls their levels within the cell.
NEDD4L interacts with a wide range of proteins, including:
- UBE2E3: This protein is a ubiquitin-conjugating enzyme that acts as a partner to E3 ligases like NEDD4L.
- NDFIP1 and NDFIP2: These proteins activate the E3 ubiquitin-protein ligase activity of NEDD4L.
- SCNN1A, SCNN1B, SCNN1G, SCN1A, SCN2A, SCN3A, SCN5A, SCN8A, SCN9A, SCN10A, CLCN5: These are components of various ion channels that NEDD4L interacts with, likely to regulate their function and turnover.
- SMAD2, SMAD3, SMAD6, SMAD7: These proteins are involved in TGF-beta signaling, and their interaction with NEDD4L contributes to the control of this pathway.
- TNK2, WNK1, SGK1: These proteins are involved in various cellular processes, including ion channel regulation and cell signaling.
- NPC2: This protein is involved in cholesterol metabolism, and its interaction with NEDD4L is mediated through the C2 domain of NEDD4L.
- ARRDC4: This protein interacts with NEDD4L and plays a role in regulating cell signaling and ion channel function.
- KCNQ1: NEDD4L interacts with KCNQ1, a potassium channel, and promotes its internalization, potentially affecting its activity.
- USP36: This protein is a deubiquitinase that can remove ubiquitin molecules, and its interaction with NEDD4L inhibits the ubiquitination of certain proteins, including NTRK1, KCNQ2, and KCNQ3.
- PRRG4: This protein interacts with NEDD4L and is involved in cell signaling.
- LDLRAD3: NEDD4L interacts with this protein, which is involved in lipoprotein metabolism.
- UBE2D2: This protein is a ubiquitin-conjugating enzyme that can act as a partner for NEDD4L.
- TTYH2 and TTYH3: These proteins are involved in ion channel regulation, and their interaction with NEDD4L contributes to their control.
- Epstein-Barr Virus LMP2A: This viral protein interacts with NEDD4L, potentially influencing the viral life cycle.
Overall, NEDD4L is a key player in numerous cellular processes, particularly those involving ubiquitination and the regulation of protein activity, cell signaling, and membrane trafficking.
NEDD4L is also known as NEDD4-2, NEDD4.2, PVNH7, RSP5, hNEDD4-2.
