MARCH5

{{Short description|Protein-coding gene in the species Homo sapiens}}

E3 ubiquitin-protein ligase MARCH5, also known as membrane-associated ring finger (C3HC4) 5, is an enzyme that, in humans, is encoded by the MARCH5 gene. It is localized in the mitochondrial outer membrane and has four transmembrane domains.{{cite journal | vauthors = Bartee E, Mansouri M, Hovey Nerenberg BT, Gouveia K, Früh K | title = Downregulation of major histocompatibility complex class I by human ubiquitin ligases related to viral immune evasion proteins | journal = Journal of Virology | volume = 78 | issue = 3 | pages = 1109–20 | date = Feb 2004 | pmid = 14722266 | pmc = 321412 | doi = 10.1128/JVI.78.3.1109-1120.2004 }}{{cite web | title = Entrez Gene: MARCH5 membrane-associated ring finger (C3HC4) 5| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54708 }}{{cite journal | vauthors = Nakamura N, Kimura Y, Tokuda M, Honda S, Hirose S | title = MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to change mitochondrial morphology | journal = EMBO Reports | volume = 7 | issue = 10 | pages = 1019–22 | date = Oct 2006 | pmid = 16936636 | doi = 10.1038/sj.embor.7400790 | pmc=1618377}}

Structure

=Gene=

The human gene MARCH5, also known as MITOL or RNF153, has 7 Exons and locates at the chromosome band 10q23.32-q23.33.

= Protein =

The human E3 ubiquitin-protein ligase MARCH5 protein, a member of the transmembrane RING‐finger protein family{{cite journal | vauthors = Lehner PJ, Hoer S, Dodd R, Duncan LM | title = Downregulation of cell surface receptors by the K3 family of viral and cellular ubiquitin E3 ligases | journal = Immunological Reviews | volume = 207 | pages = 112–25 | date = Oct 2005 | pmid = 16181331 | doi = 10.1111/j.0105-2896.2005.00314.x | s2cid = 25567313 }} 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. The theoretical PI of this protein is 9.00.{{cite web|title=Uniprot: Q9NX47 - MARH5_HUMAN|url=https://www.uniprot.org/uniprot/Q9NX47}}

Function

As an 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. MARCH5 promotes ubiquitination of Drp1 and a knockdown of MARCH5 is by RNAi led to abnormal mitochondrial fusion.{{cite journal | vauthors = Yonashiro R, Ishido S, Kyo S, Fukuda T, Goto E, Matsuki Y, Ohmura-Hoshino M, Sada K, Hotta H, Yamamura H, Inatome R, Yanagi S | title = A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics | journal = The EMBO Journal | volume = 25 | issue = 15 | pages = 3618–26 | date = Aug 2006 | pmid = 16874301 | doi = 10.1038/sj.emboj.7601249 | pmc=1538564}} Further evidences show that MARCH 5 specifically interacts with mitofusin 1, by reducing the levels of it during certain phases of the cell cycle.{{cite journal | vauthors = Park YY, Cho H | title = Mitofusin 1 is degraded at G2/M phase through ubiquitylation by MARCH5 | journal = Cell Division | volume = 7 | issue = 1 | pages = 25 | year = 2012 | pmid = 23253261 | pmc = 3542011 | doi = 10.1186/1747-1028-7-25 | doi-access = free }} 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.{{cite journal | vauthors = Park YY, Lee S, Karbowski M, Neutzner A, Youle RJ, Cho H | title = Loss of MARCH5 mitochondrial E3 ubiquitin ligase induces cellular senescence through dynamin-related protein 1 and mitofusin 1 | journal = Journal of Cell Science | volume = 123 | issue = Pt 4 | pages = 619–26 | date = Feb 2010 | pmid = 20103533 | pmc = 2818198 | doi = 10.1242/jcs.061481 }}

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.{{cite journal | vauthors = Nagashima S, Tokuyama T, Yonashiro R, Inatome R, Yanagi S | title = Roles of mitochondrial ubiquitin ligase MITOL/MARCH5 in mitochondrial dynamics and diseases | journal = Journal of Biochemistry | volume = 155 | issue = 5 | pages = 273–9 | date = May 2014 | pmid = 24616159 | doi = 10.1093/jb/mvu016 | doi-access = free }} 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.{{cite journal | vauthors = Fang L, Li J, Flammer J, Neutzner A | title = MARCH5 inactivation supports mitochondrial function during neurodegenerative stress | journal = Frontiers in Cellular Neuroscience | volume = 7 | pmid = 24133412 | doi = 10.3389/fncel.2013.00176 | year=2013 | pages=176 | pmc=3794199| doi-access = free }} 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.{{cite journal | vauthors = Shi HX, Liu X, Wang Q, Tang PP, Liu XY, Shan YF, Wang C | title = Mitochondrial ubiquitin ligase MARCH5 promotes TLR7 signaling by attenuating TANK action | journal = PLOS Pathogens | volume = 7 | issue = 5 | date = May 2011 | pmid = 21625535 | doi = 10.1371/journal.ppat.1002057 | pages=e1002057 | pmc=3098239 | doi-access = free }}

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.{{cite journal | vauthors = Wang X, Herr RA, Hansen T | title = Viral and cellular MARCH ubiquitin ligases and cancer | journal = Seminars in Cancer Biology | volume = 18 | issue = 6 | date = Dec 2008 | pmid = 18948196 | doi = 10.1016/j.semcancer.2008.09.002 | pages=441–50 | pmc=2636702}}

Gene name error in Excel

Like the other MARCH and septin genes, care must be exercised when analyzing genetic data containing the MARCH5 gene in Microsoft Excel.{{cite journal | vauthors = Zeeberg BR, Riss J, Kane DW, Bussey KJ, Uchio E, Linehan WM, Barrett JC, Weinstein JN | display-authors = 6 | title = Mistaken identifiers: gene name errors can be introduced inadvertently when using Excel in bioinformatics | journal = BMC Bioinformatics | volume = 5 | issue = 1 | pages = 80 | date = June 2004 | pmid = 15214961 | pmc = 459209 | doi = 10.1186/1471-2105-5-80 | doi-access = free }} This is due to Excel's autocorrect feature treating the MARCH gene as a date and converting it to a standard date format. The original text cannot be recovered as a result of the conversion. A 2016 study found up to 19.6% of all papers in selected journals to be affected by the gene name error.{{cite journal | vauthors = Ziemann M, Eren Y, El-Osta A | title = Gene name errors are widespread in the scientific literature | journal = Genome Biology | volume = 17 | issue = 1 | pages = 177 | date = August 2016 | pmid = 27552985 | pmc = 4994289 | doi = 10.1186/s13059-016-1044-7 | doi-access = free }} The issue can be prevented by using an alias name such as MARCHF5, prepending with an apostrophe ('), or preformatting the cell as text.