The anti-viral dynamin family member MxB participates in mitochondrial integrity.
Carcinoma, Hepatocellular
Cell Line, Tumor
DNA, Mitochondrial
/ genetics
Dynamins
/ genetics
HeLa Cells
Hepatocytes
/ metabolism
Humans
Liver Neoplasms
Mitochondria
/ metabolism
Mitochondrial Membranes
/ metabolism
Myxovirus Resistance Proteins
/ genetics
RNA Interference
RNA, Small Interfering
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
26 02 2020
26 02 2020
Historique:
received:
26
10
2018
accepted:
23
01
2020
entrez:
28
2
2020
pubmed:
28
2
2020
medline:
1
5
2020
Statut:
epublish
Résumé
The membrane deforming dynamin family members MxA and MxB are large GTPases that convey resistance to a variety of infectious viruses. During viral infection, Mx proteins are known to show markedly increased expression via an interferon-responsive promoter to associate with nuclear pores. In this study we report that MxB is an inner mitochondrial membrane GTPase that plays an important role in the morphology and function of this organelle. Expression of mutant MxB or siRNA knockdown of MxB leads to fragmented mitochondria with disrupted inner membranes that are unable to maintain a proton gradient, while expelling their nucleoid-based genome into the cytoplasm. These findings implicate a dynamin family member in mitochondrial-based changes frequently observed during an interferon-based, anti-viral response.
Identifiants
pubmed: 32102993
doi: 10.1038/s41467-020-14727-w
pii: 10.1038/s41467-020-14727-w
pmc: PMC7044337
doi:
Substances chimiques
DNA, Mitochondrial
0
MX1 protein, human
0
MX2 protein, human
0
Myxovirus Resistance Proteins
0
RNA, Small Interfering
0
Dynamins
EC 3.6.5.5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1048Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK084567
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA020735
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK044650
Pays : United States
Références
Braun, R. J. Mitochondrion-mediated cell death: dissecting yeast apoptosis for a better understanding of neurodegeneration. Front. Oncol. 2, 182 (2012).
pubmed: 23226681
pmcid: 3508457
doi: 10.3389/fonc.2012.00182
Nunnari, J. & Suomalainen, A. Mitochondria: in sickness and in health. Cell 148, 1145–1159 (2012).
pubmed: 22424226
pmcid: 5381524
doi: 10.1016/j.cell.2012.02.035
Pernas, L. & Scorrano, L. Mito-morphosis: mitochondrial fusion, fission, and cristae remodeling as key mediators of cellular function. Annu. Rev. Physiol. 78, 505–531 (2016).
pubmed: 26667075
doi: 10.1146/annurev-physiol-021115-105011
pmcid: 26667075
Kraus, F. & Ryan, M. T. The constriction and scission machineries involved in mitochondrial fission. J. Cell Sci. 130, 2953–2960 (2017).
pubmed: 28842472
doi: 10.1242/jcs.199562
Ferguson, S. M. & De Camilli, P. Dynamin, a membrane-remodelling GTPase. Nat. Rev. Mol. Cell Biol. 13, 75–88 (2012).
pubmed: 22233676
pmcid: 3519936
doi: 10.1038/nrm3266
McNiven, M. A., Cao, H., Pitts, K. R. & Yoon, Y. The dynamin family of mechanoenzymes: pinching in new places. Trends Biochem. Sci. 25, 115–120 (2000).
pubmed: 10694881
doi: 10.1016/S0968-0004(99)01538-8
Jones, S. M., Howell, K. E., Henley, J. R., Cao, H. & McNiven, M. A. Role of dynamin in the formation of transport vesicles from the trans-golgi network. Science 279, 573–577 (1998).
pubmed: 9438853
doi: 10.1126/science.279.5350.573
Harper, C. B., Popoff, M. R., McCluskey, A., Robinson, P. J. & Meunier, F. A. Targeting membrane trafficking in infection prophylaxis: dynamin inhibitors. Trends Cell Biol. 23, 90–101 (2013).
pubmed: 23164733
doi: 10.1016/j.tcb.2012.10.007
Totta, P., Busonero, C., Leone, S., Marino, M. & Acconcia, F. Dynamin II is required for 17β-estradiol signaling and autophagy-based ERα degradation. Sci. Rep. 6, 23727 (2016).
pubmed: 27009360
pmcid: 4806323
doi: 10.1038/srep23727
Fang, X. et al. Dynamin regulates autophagy by modulating lysosomal function. J. Genet. Genomics 43, 77–86 (2016).
pubmed: 26924690
doi: 10.1016/j.jgg.2015.10.005
Schulze, R. J. et al. Lipid droplet breakdown requires dynamin 2 for vesiculation of autolysosomal tubules in hepatocytes. J. Cell Biol. 203, 315–326 (2013).
pubmed: 24145164
pmcid: 3812963
doi: 10.1083/jcb.201306140
Frank, S. et al. The role of dynamin related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev. Cell 1, 515–525 (2001).
pubmed: 11703942
doi: 10.1016/S1534-5807(01)00055-7
Koch, A. et al. Dynamin-like protein 1 is involved in peroxisomal fission. J. Biol. Chem. 278, 8597–8605 (2003).
pubmed: 12499366
doi: 10.1074/jbc.M211761200
Ishihara, N., Eura, Y. & Mihara, K. Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. J. Cell Sci. 117, 6535–6546 (2004).
pubmed: 15572413
doi: 10.1242/jcs.01565
Zorzano, A., Liesa, M., Sebastian, D., Segales, J. & Palacin, M. Mitochondrial fusion proteins: dual regulators of morphology and metabolism. Semin. Cell Dev. Biol. 21, 566–574 (2010).
pubmed: 20079867
doi: 10.1016/j.semcdb.2010.01.002
Lee, H., Smith, S. B. & Yoon, Y. The short variant of the mitochondrial dynamin OPA1 maintains mitochondrial energetics and cristae structure. J. Biol. Chem. 292, 7115–7130 (2017).
pubmed: 28298442
pmcid: 5409478
doi: 10.1074/jbc.M116.762567
Cipolat, S., Martins de Brito, O., Dal Zilio, B. & Scorrano, L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc. Natl Acad. Sci. USA 101, 15927–15932 (2004).
pubmed: 15509649
doi: 10.1073/pnas.0407043101
Lee, J. E., Westrate, L. M., Wu, H., Page, C. & Voeltz, G. K. Multiple dynamin family members collaborate to drive mitochondrial division. Nature 540, 139–143 (2016).
pubmed: 27798601
pmcid: 5656044
doi: 10.1038/nature20555
Haller, O. & Kochs, G. Interferon‐iInduced Mx proteins: dynamin‐like GTPases with antiviral activity. Traffic 3, 710–717 (2002).
pubmed: 12230469
doi: 10.1034/j.1600-0854.2002.31003.x
Haller, O., Staeheli, P., Schwemmle, M. & Kochs, G. Mx GTPases: dynamin-like antiviral machines of innate immunity. Trends Microbiol. 23, 154–163 (2015).
pubmed: 25572883
doi: 10.1016/j.tim.2014.12.003
Fernandez, M., Quiroga, J. A. & Carreno, V. Hepatitis B virus downregulates the human interferon-inducible MxA promoter through direct interaction of precore/core proteins. J. Gen. Virol. 84, 2073–2082 (2003).
pubmed: 12867637
doi: 10.1099/vir.0.18966-0
Goujon, C. et al. Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection. Nature 502, 559–562 (2013).
pubmed: 24048477
doi: 10.1038/nature12542
Liu, Z. et al. The interferon-inducible MxB protein inhibits HIV-1 infection. Cell Host Microbe 14, 398–410 (2013).
pubmed: 24055605
doi: 10.1016/j.chom.2013.08.015
Buffone, C., Schulte, B., Opp, S. & Diaz-Griffero, F. Contribution of MxB oligomerization to HIV-1 capsid binding and restriction. J. Virol. 89, 3285–3294 (2015).
pubmed: 25568212
pmcid: 4337540
doi: 10.1128/JVI.03730-14
Accola, M. A., Huang, B., Al Masri, A. & McNiven, M. A. The antiviral dynamin family member, MxA, tubulates lipids and localizes to the smooth endoplasmic reticulum. J. Biol. Chem. 277, 21829–21835 (2002).
pubmed: 11916975
doi: 10.1074/jbc.M201641200
von der Malsburg, A., Abutbul-Ionita, I., Haller, O., Kochs, G. & Danino, D. Stalk domain of the dynamin-like MxA GTPase protein mediates membrane binding and liposome tubulation via the unstructured L4 loop. J. Biol. Chem. 286, 37858–37865 (2011).
pubmed: 21900240
pmcid: 3199527
doi: 10.1074/jbc.M111.249037
Stertz, S. et al. Interferon-iInduced, antiviral human MxA protein localizes to a distinct subcompartment of the smooth endoplasmic reticulum. J. Interferon Cytokine Res. 26, 650–660 (2006).
pubmed: 16978069
doi: 10.1089/jir.2006.26.650
Alvarez, F. J. D. et al. CryoEM structure of MxB reveals a novel oligomerization interface critical for HIV restriction. Sci. Adv. 3, e1701264 (2017).
pubmed: 28929138
pmcid: 5600524
doi: 10.1126/sciadv.1701264
Haller, O. Dynamins are forever: MxB inhibits HIV-1. Cell Host Microbe 14, 371–373 (2013).
pubmed: 24139395
doi: 10.1016/j.chom.2013.10.002
Fricke, T. et al. MxB binds to the HIV-1 core and prevents the uncoating process of HIV-1. Retrovirology 11, 68 (2014).
pubmed: 25123063
pmcid: 4145229
doi: 10.1186/s12977-014-0068-x
Schulte, B. et al. Restriction of HIV-1 requires the N-terminal region of MxB as a capsid-binding motif but not as a nuclear localization signal. J. Virol. 89, 8599–8610 (2015).
pubmed: 26063425
pmcid: 4524248
doi: 10.1128/JVI.00753-15
Yi, D. R. et al. Human MxB inhibits the replication of hepatitis C virus. J.Virol. 93, https://doi.org/10.1128/JVI.01285-18 (2019).
Li, N. et al. MxA inhibits hepatitis B virus replication by interaction with hepatitis B core antigen. Hepatology 56, 803–811 (2012).
pubmed: 22271421
doi: 10.1002/hep.25608
pmcid: 22271421
Melén, K. et al. Human MxB protein, an interferon-α-inducible GTPase, contains a nuclear targeting signal and is localized in the heterochromatin region beneath the nuclear envelope. J. Biol. Chem. 271, 23478–23486 (1996).
pubmed: 8798556
doi: 10.1074/jbc.271.38.23478
pmcid: 8798556
Melén, K. & Julkunen, I. Nuclear cotransport mechanism of cytoplasmic human MxB protein. J. Biol. Chem. 272, 32353–32359 (1997).
pubmed: 9405443
doi: 10.1074/jbc.272.51.32353
pmcid: 9405443
King, M. C., Raposo, G. & Lemmon, M. A. Inhibition of nuclear import and cell-cycle progression by mutated forms of the dynamin-like GTPase MxB. Proc. Natl Acad. Sci. USA 101, 8957–8962 (2004).
pubmed: 15184662
doi: 10.1073/pnas.0403167101
Yoon, Y., Krueger, E. W., Oswald, B. J. & McNiven, M. A. The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol. Cell Biol. 23, 5409–5420 (2003).
pubmed: 12861026
pmcid: 165727
doi: 10.1128/MCB.23.15.5409-5420.2003
Lee, Y. H., Tan, H. T. & Chung, M. C. Subcellular fractionation methods and strategies for proteomics. Proteomics 10, 3935–3956 (2010).
pubmed: 21080488
doi: 10.1002/pmic.201000289
Wieckowski, M. R., Giorgi, C., Lebiedzinska, M., Duszynski, J. & Pinton, P. Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells. Nat. Protoc. 4, 1582 (2009).
pubmed: 19816421
doi: 10.1038/nprot.2009.151
Wei, Y., Chiang, W.-C., Sumpter, R., Mishra, P. & Levine, B. Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell 168, 224–238.e210 (2017).
pubmed: 28017329
doi: 10.1016/j.cell.2016.11.042
pmcid: 28017329
Lam, S. S. et al. Directed evolution of APEX2 for electron microscopy and proximity labeling. Nat. Methods 12, 51 https://www.nature.com/articles/nmeth.3179#supplementary-information (2014).
pubmed: 25419960
pmcid: 4296904
doi: 10.1038/nmeth.3179
Huang, M., Camara, A. K., Stowe, D. F., Qi, F. & Beard, D. A. Mitochondrial inner membrane electrophysiology assessed by rhodamine-123 transport and fluorescence. Ann. Biomed. Eng. 35, 1276–1285 (2007).
pubmed: 17372838
pmcid: 3508792
doi: 10.1007/s10439-007-9265-2
Wong, E. D. et al. The intramitochondrial dynamin-related GTPase, Mgm1p, is a component of a protein complex that mediates mitochondrial fusion. J. Cell Biol. 160, 303 (2003).
pubmed: 12566426
pmcid: 2172654
doi: 10.1083/jcb.200209015
Scheer, U. et al. High sensitivity immunolocalization of double and single-stranded DNA by a monoclonal antibody. Eur. J. Cell Biol. 43, 358–371 (1987).
pubmed: 3305019
West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553 (2015).
pubmed: 25642965
pmcid: 4409480
doi: 10.1038/nature14156
McArthur, K. et al. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science 359, https://doi.org/10.1126/science.aao6047 (2018).
pubmed: 29472455
doi: 10.1126/science.aao6047
pmcid: 29472455
Verhelst, J., Hulpiau, P. & Saelens, X. Mx proteins: antiviral gatekeepers that restrain the uninvited. Microbiol. Mol. Biol. Rev. 77, 551–566 (2013).
pubmed: 24296571
pmcid: 3973384
doi: 10.1128/MMBR.00024-13
Elachouri, G. et al. OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution. Genome Res. 21, 12–20 (2011).
pubmed: 20974897
pmcid: 3012919
doi: 10.1101/gr.108696.110
Sundborger, A. C. et al. A dynamin mutant defines a superconstricted prefission state. Cell Rep. 8, 734–742 (2014).
pubmed: 25088425
pmcid: 4142656
doi: 10.1016/j.celrep.2014.06.054
Praefcke, G. J. & McMahon, H. T. The dynamin superfamily: universal membrane tubulation and fission molecules? Nat. Rev. Mol. Cell Biol. 5, 133–147 (2004).
pubmed: 15040446
doi: 10.1038/nrm1313
Hinshaw, J. E. Dynamin and its role in membrane fission. Annu. Rev. Cell Dev. Biol. 16, 483–519 (2000).
pubmed: 11031245
pmcid: 4781412
doi: 10.1146/annurev.cellbio.16.1.483
Cao, H., Chen, J., Awoniyi, M., Henley, J. R. & McNiven, M. A. Dynamin 2 mediates fluid-phase micropinocytosis in epithelial cells. J. Cell Sci. 120, 4167–4177 (2007).
pubmed: 18003703
doi: 10.1242/jcs.010686
Takei, K. et al. Generation of coated intermediates of clathrin-mediated endocytosis on protein-free liposomes. Cell 94, 131–141 (1998).
pubmed: 9674434
doi: 10.1016/S0092-8674(00)81228-3
Takei, K., Slepnev, V. I., Haucke, V. & De Camilli, P. Functional partnership between amphiphysin and dynamin in clathrin-mediated endocytosis. Nat. Cell Biol. 1, 33–39 (1999).
pubmed: 10559861
doi: 10.1038/9004
Nigg, P. E. & Pavlovic, J. Oligomerization and GTP-binding requirements of MxA for viral target recognition and antiviral activity against influenza A virus. J. Biol. Chem. 290, 29893–29906 (2015).
pubmed: 26507657
pmcid: 4706002
doi: 10.1074/jbc.M115.681494
Haller, O., Gao, S., von der Malsburg, A., Daumke, O. & Kochs, G. Dynamin-like MxA GTPase: structural insights into oligomerization and implications for antiviral activity. J. Biol. Chem. 285, 28419–28424 (2010).
pubmed: 20538602
pmcid: 2937866
doi: 10.1074/jbc.R110.145839
Mitchell, P. S., Young, J. M., Emerman, M. & Malik, H. S. Evolutionary analyses suggest a function of MxB immunity proteins beyond lentivirus restriction. PLoS Pathog. 11, e1005304 (2015).
pubmed: 26658285
pmcid: 4687636
doi: 10.1371/journal.ppat.1005304
Crameri, M. et al. MxB is an interferon-induced restriction factor of human herpesviruses. Nat. Commun. 9, 1980 (2018).
pubmed: 29773792
pmcid: 5958057
doi: 10.1038/s41467-018-04379-2
Yu-Wai-Man, P. et al. OPA1 mutations cause cytochrome c oxidase deficiency due to loss of wild-type mtDNA molecules. Hum. Mol. Genet. 19, 3043–3052 (2010).
pubmed: 20484224
pmcid: 2901142
doi: 10.1093/hmg/ddq209
Guan, K., Farh, L., Marshall, T. K. & Deschenes, R. J. Normal mitochondrial structure and genome maintenance in yeast requires the dynamin-like product of the MGM1 gene. Curr. Genet. 24, 141–148 (1993).
pubmed: 7916673
doi: 10.1007/BF00324678
Meeusen, S. et al. Mitochondrial inner-membrane fusion and crista maintenance requires the dynamin-related GTPase Mgm1. Cell 127, 383–395 (2006).
pubmed: 17055438
doi: 10.1016/j.cell.2006.09.021
Song, Z., Ghochani, M., McCaffery, J. M., Frey, T. G. & Chan, D. C. Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion. Mol. Biol. Cell 20, 3525–3532 (2009).
pubmed: 19477917
pmcid: 2719570
doi: 10.1091/mbc.e09-03-0252
Ernster, L. & Schatz, G. Mitochondria: a historical review. J. Cell Biol. 91, 227 s–255 s (1981).
doi: 10.1083/jcb.91.3.227s
Cogliati, S., Enriquez, J. A. & Scorrano, L. Mitochondrial cristae: where beauty meets functionality. Trends Biochem. Sci. 41, 261–273 (2016).
pubmed: 26857402
doi: 10.1016/j.tibs.2016.01.001
Bleazard, W. et al. The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast. Nat. Cell Biol. 1, 298–304 (1999).
pubmed: 10559943
pmcid: 3739991
doi: 10.1038/13014
Yoon, Y., Pitts, K. R., Dahan, S. & McNiven, M. A. A novel dynamin-like protein associates with cytoplasmic vesicles and tubules of the endoplasmic reticulum in mammalian cells. J. Cell Biol. 140, 779–793 (1998).
pubmed: 9472031
pmcid: 2141745
doi: 10.1083/jcb.140.4.779
Badley, A. D., Roumier, T., Lum, J. J. & Kroemer, G. Mitochondrion-mediated apoptosis in HIV−1 infection. Trends Pharm. Sci. 24, 298–305 (2003).
pubmed: 12823956
doi: 10.1016/S0165-6147(03)00125-1
Arnoult, D., Petit, F., Lelievre, J. D. & Estaquier, J. Mitochondria in HIV−1-induced apoptosis. Biochem. Biophys. Res. Commun. 304, 561–574 (2003).
pubmed: 12729591
doi: 10.1016/S0006-291X(03)00629-6
Ackermann, W. W. & Kurtz, H. The relation of herpes virus to host cell mitochondria. J. Exp. Med. 96, 151–157 (1952).
pubmed: 14955571
pmcid: 2136132
doi: 10.1084/jem.96.2.151
Saffran, H. A., Pare, J. M., Corcoran, J. A., Weller, S. K. & Smiley, J. R. Herpes simplex virus eliminates host mitochondrial DNA. EMBO Rep. 8, 188–193 (2007).
pubmed: 17186027
doi: 10.1038/sj.embor.7400878
Duguay, B. A. et al. Elimination of mitochondrial DNA is not required for herpes simplex virus 1 replication. J. Virol. 88, 2967–2976 (2014).
pubmed: 24371054
pmcid: 3958086
doi: 10.1128/JVI.03129-13
Fang, C., Wei, X. & Wei, Y. Mitochondrial DNA in the regulation of innate immune responses. Protein Cell 7, 11–16 (2016).
pubmed: 26498951
doi: 10.1007/s13238-015-0222-9
West, A. P. & Shadel, G. S. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat. Rev. Immunol. 17, 363–375 (2017).
pubmed: 28393922
doi: 10.1038/nri.2017.21
Hickey, R. D. et al. Curative ex vivo liver-directed gene therapy in a pig model of hereditary tyrosinemia type 1. Sci. Transl. Med. 8, 349ra399 (2016).
doi: 10.1126/scitranslmed.aaf3838
Nakabayashi, H., Taketa, K., Miyano, K., Yamane, T. & Sato, J. Growth of human hepatoma cell lines with differentiated functions in chemically defined medium. Cancer Res. 42, 3858–3863 (1982).
pubmed: 6286115
Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671–675 (2012).
pubmed: 5554542
pmcid: 5554542
doi: 10.1038/nmeth.2089
Bolte, S. & Cordelieres, F. P. A guided tour into subcellular colocalization analysis in light microscopy. J. Microsc. 224, 213–232 (2006).
pubmed: 17210054
doi: 10.1111/j.1365-2818.2006.01706.x