MUL1: Difference between revisions
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=== Protein === | === Protein === | ||
The human protein Mitochondrial E3 ubiquitin protein ligase 1 is ~40 kDa in size and composed of 352 amino acids.<ref name=pmid18591963/><ref name=pmid18213395>{{cite journal | vauthors = Li W, Bengtson MH, Ulbrich A, Matsuda A, Reddy VA, Orth A, Chanda SK, Batalov S, Joazeiro CA | title = Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling | journal = PLOS ONE | volume = 3 | issue = 1 | pages = e1487 | date = 23 January 2008 | pmid = 18213395 | doi = 10.1371/journal.pone.0001487 | pmc=2198940}}</ref><ref name=uniprot>{{cite web|title=Uniprot: Q969V5 - MUL1_HUMAN|url= | The human protein Mitochondrial E3 ubiquitin protein ligase 1 is ~40 kDa in size and composed of 352 amino acids.<ref name=pmid18591963/><ref name=pmid18213395>{{cite journal | vauthors = Li W, Bengtson MH, Ulbrich A, Matsuda A, Reddy VA, Orth A, Chanda SK, Batalov S, Joazeiro CA | title = Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling | journal = PLOS ONE | volume = 3 | issue = 1 | pages = e1487 | date = 23 January 2008 | pmid = 18213395 | doi = 10.1371/journal.pone.0001487 | pmc=2198940}}</ref><ref name=uniprot>{{cite web|title=Uniprot: Q969V5 - MUL1_HUMAN|url=https://www.uniprot.org/uniprot/Q969V5}}</ref> The calculated theoretical pI of this protein is 7.28.<ref name="Kozlowski">{{cite journal|last1=Kozlowski|first1=LP|title=IPC - Isoelectric Point Calculator.|journal=Biology Direct|date=21 October 2016|volume=11|issue=1|pages=55|doi=10.1186/s13062-016-0159-9|pmid=27769290| url =http://isoelectric.ovh.org|pmc=5075173}}</ref> MUL1 contains Ring domains at both its [[N-terminal]] and [[C-terminal]], which are both exposed to the [[cytosol]].<ref name=pmid18207745/> The C-terminal Ring finger domain is homologous to that found in the [[CD47|IAP]] family members and responsible for its [[E3 ligase]] activity.<ref name=pmid18591963/> In addition to these Ring domains, 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.<ref name=pmid18207745/><ref name = "Jenkins _2013">{{cite journal | vauthors = Jenkins K, Khoo JJ, Sadler A, Piganis R, Wang D, Borg NA, Hjerrild K, Gould J, Thomas BJ, Nagley P, Hertzog PJ, Mansell A | title = Mitochondrially localised MUL1 is a novel modulator of antiviral signaling | journal = Immunology and Cell Biology | volume = 91 | issue = 4 | pages = 321–30 | date = Apr 2013 | pmid = 23399697 | doi = 10.1038/icb.2013.7 }}</ref> Though it lacks a conserved N-terminal signal peptide or mitochondrial [[targeting sequence]], its transmembrane domains have been observed to influence its trafficking and insertion into the mitochondrial membrane.<ref name=pmid18213395/><ref name = "Jenkins _2013"/> | ||
== Function == | == Function == | ||
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Mitochondrial E3 ubiquitin protein ligase 1 (MUL1) is an enzyme that in humans is encoded by the MUL1 gene on chromosome 1. This enzyme localizes to the outer mitochondrial membrane, where it regulates mitochondrial morphology and apoptosis through multiple pathways, including the Akt, JNK, and NF-κB.[1][2][3] Its proapopototic function thus implicates it in cancer and Parkinson’s disease.[3][4]
Structure
Gene
The gene MUL1 encodes one of the E3 ubiquitin ligases. The human gene MUL1 has 5 exons and is located at chromosome band 1p36.12.[5]
Protein
The human protein Mitochondrial E3 ubiquitin protein ligase 1 is ~40 kDa in size and composed of 352 amino acids.[3][6][7] The calculated theoretical pI of this protein is 7.28.[8] MUL1 contains Ring domains at both its N-terminal and C-terminal, which are both exposed to the cytosol.[2] The C-terminal Ring finger domain is homologous to that found in the IAP family members and responsible for its E3 ligase activity.[3] In addition to these Ring domains, 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.[2][9] Though it lacks a conserved N-terminal signal peptide or mitochondrial targeting sequence, its transmembrane domains have been observed to influence its trafficking and insertion into the mitochondrial membrane.[6][9]
Function
Exhibits weak E3 ubiquitin-protein ligase activity. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates. Can ubiquitinate AKT1 preferentially at 'Lys-284' involving 'Lys-48'-linked polyubiquitination and seems to be involved in regulation of Akt signaling by targeting phosphorylated Akt to proteosomal degradation.[10] Proposed to preferentially act as a SUMO E3 ligase at physiological concentrations.[1] Is anchored in the outer mitochondrial membrane.[2] Plays a role in the control of mitochondrial morphology. Promotes mitochondrial fragmentation and influences mitochondrial localization.[1][2] The function may implicate its ability to sumoylate DNM1L.[1] Has been observed to shuttle between the mitochondria and peroxisome, where it may also help regulate peroxisome fission.[2] Inhibits cell growth.[3] When overexpressed, activates JNK through MAP3K7/TAK1 and induces caspase-dependent apoptosis.[3] Involved in the modulation of innate immune defense against viruses by inhibiting DDX58-dependent antiviral response. Can mediate DDX58 sumoylation and disrupt its polyubiquitination.[7][9] Can also activate NF-κB to initiate mitochondria-to-nucleus signaling under stress.[3]
Clinical significance
As aforementioned, MUL1 encodes for an enzyme which is located on outer mitochondrial membrane, where it regulates mitochondrial morphology and apoptosis.[1][2][3] Specifically, this enzyme has pro-apoptotic functions.
An apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[11] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
Though MUL1 is highly expressed in most human tissues during normal conditions, it is found to be missing in cancer cells derived from lung, liver, colon, and kidney. This observation suggests that the antiapoptotic MUL1 serves as a tumor suppressor and is thus downregulated in cancer cells.[3]
Experiments in drosophila and mammalian systems reveal that MUL1 binds and ubiquitinylates mitofusin, which then allows it to indirectly regulate the PINK1/parkin pathway. Thus, this protein can rescue the phenotypes of PINK1 or parkin knockout mice display, which elucidates why only subtle dopaminergic neuronal degeneration or mitochondrial morphology changes have been observed. MUL1 is then a promising therapeutic target for treating Parkinson’s disease.[4]
Mul1 has also been implicated as a modulator of antiviral signaling.[9] MUL1 is localized to the mitochondria where it interacts with mitochondrial antiviral signaling and catalyzes RIG-I post-translational modifications that inhibit RIG-I-dependent cell signaling. Accordingly, depletion of MUL1 potentiates RIG-I mediated nuclear factor-kappa B (NF-κB) and interferon (IFN) β reporter activity. Moreover, depletion of MUL1 boosts the antiviral response and increased pro inflammatory cytokines following challenge with the RNA mimetic poly I:C and Sendai virus. It is therefore submitted that MUL1 is a novel regulator of the RIG-I-like receptor-dependent antiviral response, that otherwise functions to limit inflammation.[9] In addition, as a regulator of viral-induced interferon production and proinflammatory cytokine induction, MUL1 functions through mitochondrial antiviral signaling proteins to inhibit RIG-1-induced signaling and mediate the cell’s antiviral and inflammatory response.[9]
Interactions
MUL1 is known to interact with:
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Braschi E, Zunino R, McBride HM (Jul 2009). "MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission". EMBO Reports. 10 (7): 748–54. doi:10.1038/embor.2009.86. PMC 2727426. PMID 19407830.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Neuspiel M, Schauss AC, Braschi E, Zunino R, Rippstein P, Rachubinski RA, Andrade-Navarro MA, McBride HM (Jan 2008). "Cargo-selected transport from the mitochondria to peroxisomes is mediated by vesicular carriers". Current Biology. 18 (2): 102–8. doi:10.1016/j.cub.2007.12.038. PMID 18207745.
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 Zhang B, Huang J, Li HL, Liu T, Wang YY, Waterman P, Mao AP, Xu LG, Zhai Z, Liu D, Marrack P, Shu HB (Sep 2008). "GIDE is a mitochondrial E3 ubiquitin ligase that induces apoptosis and slows growth". Cell Research. 18 (9): 900–10. doi:10.1038/cr.2008.75. PMC 3156110. PMID 18591963.
- ↑ 4.0 4.1 4.2 Yun J, Puri R, Yang H, Lizzio MA, Wu C, Sheng ZH, Guo M (4 June 2014). "MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin". eLife. 3: e01958. doi:10.7554/elife.01958. PMC 4044952. PMID 24898855.
- ↑ "Entrez Gene: MUL1 mitochondrial E3 ubiquitin protein ligase 1".
- ↑ 6.0 6.1 Li W, Bengtson MH, Ulbrich A, Matsuda A, Reddy VA, Orth A, Chanda SK, Batalov S, Joazeiro CA (23 January 2008). "Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling". PLOS ONE. 3 (1): e1487. doi:10.1371/journal.pone.0001487. PMC 2198940. PMID 18213395.
- ↑ 7.0 7.1 "Uniprot: Q969V5 - MUL1_HUMAN".
- ↑ Kozlowski, LP (21 October 2016). "IPC - Isoelectric Point Calculator". Biology Direct. 11 (1): 55. doi:10.1186/s13062-016-0159-9. PMC 5075173. PMID 27769290.
- ↑ 9.0 9.1 9.2 9.3 9.4 9.5 Jenkins K, Khoo JJ, Sadler A, Piganis R, Wang D, Borg NA, Hjerrild K, Gould J, Thomas BJ, Nagley P, Hertzog PJ, Mansell A (Apr 2013). "Mitochondrially localised MUL1 is a novel modulator of antiviral signaling". Immunology and Cell Biology. 91 (4): 321–30. doi:10.1038/icb.2013.7. PMID 23399697.
- ↑ Bae S, Kim SY, Jung JH, Yoon Y, Cha HJ, Lee H, Kim K, Kim J, An IS, Kim J, Um HD, Park IC, Lee SJ, Nam SY, Jin YW, Lee JH, An S (May 2012). "Akt is negatively regulated by the MULAN E3 ligase". Cell Research. 22 (5): 873–85. doi:10.1038/cr.2012.38. PMC 3343661. PMID 22410793.
- ↑ Kerr JF, Wyllie AH, Currie AR (Aug 1972). "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics". British Journal of Cancer. 26 (4): 239–57. doi:10.1038/bjc.1972.33. PMC 2008650. PMID 4561027.