دورية أكاديمية
The human cytomegalovirus protein pUL13 targets mitochondrial cristae architecture to increase cellular respiration during infection.
| العنوان: | The human cytomegalovirus protein pUL13 targets mitochondrial cristae architecture to increase cellular respiration during infection. |
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| المؤلفون: | Betsinger CN; Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, NJ 08544., Jankowski CSR; Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, NJ 08544., Hofstadter WA; Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, NJ 08544., Federspiel JD; Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, NJ 08544., Otter CJ; Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, NJ 08544., Jean Beltran PM; Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, NJ 08544., Cristea IM; Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, NJ 08544 icristea@princeton.edu. |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Aug 10; Vol. 118 (32). |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | Cytomegalovirus/*physiology , Cytomegalovirus Infections/*metabolism , Mitochondria/*metabolism , Mitochondria/*virology , Viral Proteins/*metabolism, Cytomegalovirus/metabolism ; Cytomegalovirus/pathogenicity ; Cytomegalovirus Infections/virology ; Electron Transport ; Host-Pathogen Interactions/physiology ; Humans ; Mitochondria/ultrastructure ; Oxidative Phosphorylation ; Viral Proteins/genetics ; Virus Replication |
| مستخلص: | Viruses modulate mitochondrial processes during infection to increase biosynthetic precursors and energy output, fueling virus replication. In a surprising fashion, although it triggers mitochondrial fragmentation, the prevalent pathogen human cytomegalovirus (HCMV) increases mitochondrial metabolism through a yet-unknown mechanism. Here, we integrate molecular virology, metabolic assays, quantitative proteomics, and superresolution confocal microscopy to define this mechanism. We establish that the previously uncharacterized viral protein pUL13 is required for productive HCMV replication, targets the mitochondria, and functions to increase oxidative phosphorylation during infection. We demonstrate that pUL13 forms temporally tuned interactions with the mitochondrial contact site and cristae organizing system (MICOS) complex, a critical regulator of cristae architecture and electron transport chain (ETC) function. Stimulated emission depletion superresolution microscopy shows that expression of pUL13 alters cristae architecture. Indeed, using live-cell Seahorse assays, we establish that pUL13 alone is sufficient to increase cellular respiration, not requiring the presence of other viral proteins. Our findings address the outstanding question of how HCMV targets mitochondria to increase bioenergetic output and expands the knowledge of the intricate connection between mitochondrial architecture and ETC function. Competing Interests: The authors declare no competing interest. |
| References: | J Virol. 2011 Feb;85(4):1573-80. (PMID: 21147915) Curr Top Microbiol Immunol. 2008;325:417-70. (PMID: 18637519) PLoS Pathog. 2006 Dec;2(12):e132. (PMID: 17173481) Nat Methods. 2013 Aug;10(8):730-6. (PMID: 23921808) J Virol. 2010 Feb;84(4):1867-73. (PMID: 19939921) Arch Virol. 2013 Feb;158(2):473-7. (PMID: 23065125) EMBO J. 2020 Jul 15;39(14):e104105. (PMID: 32567732) EMBO J. 2019 Nov 15;38(22):e101056. (PMID: 31609012) Mol Cell Biol. 2002 Apr;22(7):2136-46. (PMID: 11884601) Elife. 2015 May 21;4:. (PMID: 25997101) Nat Commun. 2014;5:3103. (PMID: 24476986) Biochim Biophys Acta. 2015 Feb;1847(2):171-181. (PMID: 25449966) Elife. 2015 Apr 28;4:. (PMID: 25918844) EMBO J. 2011 Oct 18;30(21):4356-70. (PMID: 22009199) Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12396-401. (PMID: 14519856) Nat Commun. 2017 May 31;8:15258. (PMID: 28561061) Cell Syst. 2016 Oct 26;3(4):361-373.e6. (PMID: 27641956) Front Microbiol. 2014 May 19;5:218. (PMID: 24904534) J Biol Chem. 1967 Jul 10;242(13):3239-41. (PMID: 6027798) PLoS One. 2016 Aug 01;11(8):e0160258. (PMID: 27479602) J Virol. 2013 Aug;87(15):8481-92. (PMID: 23720730) PLoS One. 2015 Mar 17;10(3):e0120213. (PMID: 25781180) J Biol Chem. 2011 Jan 28;286(4):2918-32. (PMID: 21081504) Nat Biotechnol. 2008 Oct;26(10):1179-86. (PMID: 18820684) Biochem J. 2004 Aug 15;382(Pt 1):331-6. (PMID: 15139850) Mitochondrion. 2011 Nov;11(6):935-45. (PMID: 21907833) Front Cell Infect Microbiol. 2019 Mar 04;9:42. (PMID: 30886834) Sci Rep. 2015 Jan 23;5:7990. (PMID: 25612828) J Virol. 2019 Oct 15;93(21):. (PMID: 31391267) Sci Rep. 2015 Nov 04;5:16064. (PMID: 26530328) Science. 2007 Jun 1;316(5829):1345-8. (PMID: 17540903) Biochim Biophys Acta. 1999 Feb 9;1410(2):103-23. (PMID: 10076021) Expert Rev Anti Infect Ther. 2004 Dec;2(6):881-94. (PMID: 15566332) Rev Med Virol. 2010 Jul;20(4):202-13. (PMID: 20564615) J Virol. 2003 Jan;77(1):631-41. (PMID: 12477866) Biochim Biophys Acta. 2012 Oct;1817(10):1833-8. (PMID: 22409868) Virology. 2015 May;479-480:609-18. (PMID: 25812764) FEBS Lett. 2003 Jul 10;546(2-3):355-8. (PMID: 12832068) Biochim Biophys Acta. 2015 Oct;1853(10 Pt B):2822-33. (PMID: 25595529) Bioinformatics. 2010 Apr 1;26(7):966-8. (PMID: 20147306) Cell Rep. 2018 Nov 13;25(7):1786-1799.e4. (PMID: 30428348) mBio. 2016 Mar 29;7(2):e00029. (PMID: 27025248) J Virol. 2020 Jan 6;94(2):. (PMID: 31694945) Cell Struct Funct. 1998 Apr;23(2):85-93. (PMID: 9669036) Front Pharmacol. 2019 Feb 19;10:98. (PMID: 30837873) Cell Metab. 2008 Nov;8(5):384-98. (PMID: 19046570) Nat Methods. 2011 Jan;8(1):70-3. (PMID: 21131968) Cell Rep. 2020 Jul 28;32(4):107943. (PMID: 32726614) Hepatology. 2009 Aug;50(2):378-86. (PMID: 19591124) |
| معلومات مُعتمدة: | F31 AI154796 United States AI NIAID NIH HHS; R01 GM114141 United States GM NIGMS NIH HHS; T32 GM007388 United States GM NIGMS NIH HHS |
| فهرسة مساهمة: | Keywords: HCMV; metabolism; mitochondria; pUL13; proteomics |
| المشرفين على المادة: | 0 (Viral Proteins) |
| تواريخ الأحداث: | Date Created: 20210804 Date Completed: 20211217 Latest Revision: 20220716 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC8364163 |
| DOI: | 10.1073/pnas.2101675118 |
| PMID: | 34344827 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
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| DOI: | 10.1073/pnas.2101675118 |