E3 ubiquitin-protein ligase MARCH5, also known as membrane-associated ring finger (C3HC4) 5, is an enzyme that, in humans, is encoded by the MARCH5gene. It is localized in the mitochondrial outer membrane and has four transmembrane domains.[1][2][3]
The human gene MARCH5, also known as MITOL or RNF153, has 7 Exons and locates at the chromosome band 10q23.32-q23.33.[2]
Protein
The human E3 ubiquitin-protein ligase MARCH5 protein, a member of the transmembrane RING‐finger protein family[4] is 31 kDa in size and composed of 278 amino acids with a N-terminal Zinc-finger domain at amino acid sequence 6-75 and four C-terminal transmembrane spans.[3] The theoretical PI of this protein is 9.00.[5]
Function
As a E3 ubiquitin ligases, enzyme MARCH 5 catalyzes the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to an identified protein substrate. MARCH5 was firstly identified as a mitofusin 2- and Drp1-binding protein.[3] MARCH5 promotes ubiquitination of Drp1 and a knockdown of MARCH5 is by RNAi led to abnormal mitochondrial fusion.[6] Further evidences show that MARCH 5 specifically interacts with mitofusin 1, by reducing the levels of it during certain phases of the cell cycle.[7] Given the facts that MARCH5 regulates the protein proteostasis of Drp1, mitofusin 1, and mitofusin 2 that are pivotal regulators of mitochondrial fusion and fission, MARCH5 is critical for the regulation of standard mitochondria morphology, and deficiencies in it promote cellular senescence.[8]
Clinical significance
Considering that both Drp1 and MAP1B are substrates for MITOL, MITOL is thought to play a protective role against nitrosative stress-mediated disruption of mitochondrial dynamics such as morphological stability and transport of mitochondria. As significantly decreased expression of MITOL occurs in response to ageing in normal tissues, MITOL may control ageing by regulating the production of ROS in mitochondria.[9] From a pathological perspective, in a neuronal cell model, dominant-negative MARCH5 prevents mitochondrial fragmentation during neurodegenerative stress induced by the neuron-specific reactive oxygen generator 6-hydroxydopamine, the complex I inhibitor rotenone or Alzheimer's-related amyloid beta peptide. MARCH5 is also involved in the removal of proteins associated with specific neurodegenerative disorders such as ataxin-3 in Machado–Joseph disease or mSOD1 in amyotrophic lateral sclerosis likely supporting mitochondrial function.[10] MARCH5 has also been linked to toll-like receptors (TLRs), which recognize distinct pathogen-associated molecular patterns and play a critical role in the innate immune response.[11]
Ubiquitin-dependent degradation pathways have clear cancer relevance due to their integral involvement in protein quality control, regulation of immune responses, signal transduction, and cell cycle regulation.[12]