Fatty Acid Elongase 7 Catalyzes Lipidome Remodeling Essential for Human Cytomegalovirus Replication
Open accessAbstract
Human cytomegalovirus (HCMV) infection rewires host-cell metabolism, upregulating flux from glucose into acetyl-CoA to feed fatty acid metabolism, with saturated very-long-chain fatty acids (VLFCAs) required for production of infectious virion progeny. The human genome encodes seven elongase enzymes (ELOVL) that extend long-chain fatty acids into VLCFA. Here, we identify ELOVL7 as pivotal for HCMV infection. HCMV induces ELOVL7 by more than 150-fold. This induction is dependent on mTOR and SREBP-1. ELOVL7 knockdown or mTOR inhibition impairs HCMV-induced fatty acid elongation, HCMV particle release, and infectivity per particle. ELOVL7 overexpression enhances HCMV replication. During HCMV infection, mTOR activity is maintained by the viral protein pUL38. Expression of pUL38 is sufficient to induce ELOVL7, and pUL38-deficient virus is partially defective in ELOVL7 induction and fatty acid elongation. Thus, through its ability to modulate mTOR and SREBP-1, HCMV induces ELOVL7 to synthesize the saturated VLCFA required for efficient virus replication.
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VLCFAs accumulate upon human cytomegalovirus infection.
“Infection with HCMV results in markedly elevated cellular levels of saturated very long-chain fatty acids (VLCFAs, ≥ C22), with C26:0 as the most abundant VLCFA of the viral envelope5,6.”
From Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response (2022) · cites this paper as [6]
Very long-chain fatty acids are critical for human cytomegalovirus replication.
“Very long-chain fatty acids (VLCFA) are critical for human cytomegalovirus replication and accumulate upon infection.”
From Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response (2022) · cites this paper as [6]
VLCFAs are enriched upon HCMV infection by targeting the fatty acid elongation process.
“Whereas previous reports demonstrated that VLCFAs are enriched upon HCMV infection by targeting the fatty acid elongation process5,6”
From Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response (2022) · cites this paper as [6]
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Cites
ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis
Ohno, Y., Suto, S., Yamanaka, M., Mizutani, Y., Mitsutake, S., Igarashi, Y., Sassa, T., & Kihara, A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1005572107 · Cited by 382 · see citing works
Identification and expression of mammalian long‐chain PUFA elongation enzymes
Leonard, A. E., Kelder, B., Bobik, E. G., Chuang, L., Lewis, C. J., Kopchick, J. J., Mukerji, P., & Huang, Y. (2002) · Lipids · doi:10.1007/s11745-002-0955-6 · Cited by 209 · see citing works
The role of ELOVL1 in very long-chain fatty acid homeostasis and X-linked adrenoleukodystrophy
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Weinhofer, I., Buda, A., Kunze, M., Palfi, Z., Traunfellner, M., Hesse, S., Villoria-Gonzalez, A., Hofmann, J., Hametner, S., Regelsberger, G., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-03867-y · Cited by 20 · see citing works
- Authors
- Purdy, J. G., Shenk, T., & Rabinowitz, J. D.
- Affiliations
- Princeton University (US)
- Corresponding author
- Rabinowitz, Joshua D.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 10
- Issue
- 8
- Pages
- 1375-1385
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4354725
- OpenAlex
- W1985380245
- Cited by
- 103
- References
- 4
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 10 · 2023: 5 · 2022: 6 · 2021: 12 · 2020: 5 · 2019: 22 · 2018: 10 · 2017: 9 · 2016: 2 · 2015: 2
- FWCI
- 6.02
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc)
- PubMed Central (acceptedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American Heart Association
- National Institutes of Health
- National Cancer Institute (CA 82396, R01CA082396)
- National Institute of General Medical Sciences (P50GM071508, GM71508)
- National Institute of Allergy and Infectious Diseases (R01AI097382, AI78063, R01AI078063)
- Topics
- Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- human cytomegalovirus, ELOVL7, fatty acid elongation, very long chain fatty acids, mTOR, SREBP1, viral replication, virion production, host-virus interaction
- MeSH terms
- Fatty Acid Elongases, Acetyltransferases, Cell Line, Cytomegalovirus, Fatty Acids, Humans, Viral Proteins, Virion, Virus Replication, RNA Interference, RNA, Small Interfering, Sterol Regulatory Element Binding Protein 1, Biocatalysis, TOR Serine-Threonine Kinases
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