MUL1
Description
The MUL1 (mitochondrial E3 ubiquitin protein ligase 1) is a protein-coding gene located on chromosome 1.
Mitochondrial E3 ubiquitin protein ligase 1 (MUL1) is an enzyme encoded by the MUL1 gene on chromosome 1 in humans. It localizes to the outer mitochondrial membrane, regulating mitochondrial morphology and apoptosis through multiple pathways, including Akt, JNK, and NF-κB. Its proapoptotic function implicates it in cancer and Parkinson's disease. The MUL1 gene contains 5 exons and is located at chromosome band 1p36.12. The protein is ~40 kDa in size, composed of 352 amino acids, and has a theoretical pI of 7.28. It contains Ring domains at both its N-terminal and C-terminal, which are both exposed to the cytosol. The C-terminal Ring finger domain is homologous to that found in the IAP family members and responsible for its E3 ligase activity. MUL1 is predicted to have two mitochondrial transmembrane helices, with the first domain serving as the primary anchor for the rest of the exposed protein. Though it lacks a conserved N-terminal signal peptide or mitochondrial targeting sequence, its transmembrane domains influence its trafficking and insertion into the mitochondrial membrane.
MUL1 exhibits weak E3 ubiquitin-protein ligase activity, accepting ubiquitin from an E2 ubiquitin-conjugating enzyme and transferring it to targeted substrates. It can ubiquitinate AKT1 at Lys-284, leading to its degradation and regulation of Akt signaling. MUL1 also mediates polyubiquitination of TP53 at Lys-24, targeting it for degradation and reducing TP53 levels in the cytoplasm and mitochondrion. At physiological concentrations, MUL1 is proposed to act preferentially as a SUMO E3 ligase. MUL1 plays a role in controlling mitochondrial morphology by promoting fragmentation and influencing mitochondrial localization. It likely promotes mitochondrial fission by negatively regulating the fusion proteins MFN1 and MFN2, acting in parallel to the PRKN/PINK1 pathway. MUL1 may also be involved in sumoylation of the membrane fission protein DNM1L. It inhibits cell growth and, when overexpressed, activates JNK through MAP3K7/TAK1, inducing caspase-dependent apoptosis. MUL1 participates in modulating innate immune defense against viruses by inhibiting RIGI-dependent antiviral response, mediating RIGI sumoylation and disrupting its polyubiquitination.
MUL1 is also known as C1orf166, GIDE, MAPL, MULAN, RNF218.
