Ferritinophagy Rewires Carnitine‐Dependent Lipid Metabolism to Inhibit PRRSV and IAV Replication
Source abstract
Abstract
ABSTRACT Ferritinophagy is crucial for maintaining iron homeostasis and regulating iron‐dependent viral replication. This study demonstrates that ferritinophagy reprograms carnitine‐dependent lipid metabolism by impairing Fe‐S clusters biogenesis, thereby inhibiting iron‐dependent viral replication. Specifically, NCOA4‐mediated ferritinophagy disrupts Fe‐S clusters assembly through the autophagic degradation of MMS19, leading to mitochondrial metabolic remodeling and suppression of carnitine biosynthesis. Carnitine deficiency subsequently destabilizes the proteins TMED10, HDLBP, and RAB40C via specific amino acid residues (Asp78, Leu336, and Glu154, respectively), and we reveal that carnitine directly stabilizes these lipid droplet‐associated proteins, promoting lipid droplet formation. Collectively, these changes orchestrate an iron‐lipid metabolic axis that inhibits the replication of diverse PRRSV strains as well as influenza A virus (IAV). Conversely, PRRSV counteracts this antiviral mechanism by promoting autophagic degradation of NCOA4 via K63‐linked ubiquitination, a process in which the viral protein Nsp5 recruits the E3 ligase adaptor DDB1 to mediate ubiquitination. Our findings establish NCOA4 as a link between ferritinophagy and lipid metabolic reprogramming, revealing a novel antiviral pathway and providing foundational insights for developing innovative antiviral strategies.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Bacteriophages and microbial interactions · interferon and immune responses · RNA modifications and cancer
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
School of Advanced Agricultural Sciences Peking University Beijing China
Longhu Laboratory Zhengzhou University Zhengzhou China
College of Veterinary Medicine Northwest A&F University Yangling China
International Joint Research Center of National Animal Immunology College of Veterinary Medicine Henan Agricultural University Zhengzhou China
Institute of Reproductive Medicine School of Medicine Nantong University Nantong China
Hubei Hongshan Laboratory College of Animal Science and Technology Huazhong Agricultural University Wuhan China
Institute for Animal Health (Key Laboratory of Animal Immunology) Henan Academy of Agricultural Sciences Zhengzhou China
Funding
National Natural Science Foundation of China · China Postdoctoral Science Foundation · National Key Research and Development Program of China
References (58)
Show source-provided references
1. p21‐mediated RNR2 Repression Restricts HIV‐1 Replication in Macrophages by Inhibiting dNTP Biosynthesis Pathway10.1073/pnas.1306719110 ↗
2. Fe‐S Cofactors in the SARS‐CoV‐2 RNA‐dependent RNA Polymerase Are Potential Antiviral Targets10.1126/science.abi5224 ↗
3. Iron Deficiency Impairs Dendritic Cell Development and Function, Compromising Host Anti‐Infection Capacity10.1002/advs.202408348 ↗
4. Dietary Iron Deficiency Impaired Peripheral Immunity but Did Not Alter Brain Microglia in PRRSV‐Infected Neonatal Piglets10.3389/fimmu.2018.03150 ↗
5. The Hemagglutinin of Influenza A Virus Induces Ferroptosis to Facilitate Viral Replication10.1002/advs.202404365 ↗
6. Viral Infection and Iron Metabolism10.1038/nrmicro1930 ↗
7. Viruses Hijack FPN1 to Disrupt Iron Withholding and Suppress Host Defense10.1038/s41467-025-60031-w ↗
8. The Role of Iron in Normal and Impaired Testicular Function
9. Ferritinophagy in the Etiopathogenic Mechanism of Related Diseases10.1016/j.jnutbio.2023.109339 ↗
10. Key Role of Heavy Metals Toxicity10.1007/s00204-025-03963-y ↗
11. The Interplay between Lipid Droplets and Virus Infection10.1002/jmv.28967 ↗
12. Intracellular Lipid Droplet Accumulation Occurs Early Following Viral Infection and Is Required for an Efficient Interferon Response10.1038/s41467-021-24632-5 ↗
13. ATG14 targets Lipid Droplets and Acts as an Autophagic Receptor for syntaxin18‐regulated Lipid Droplet Turnover10.1038/s41467-024-44978-w ↗
14. n Intertwined Relationship
15. Calcium‐mediated Mitochondrial Fission and Mitophagy Drive Glycolysis to Facilitate Arterivirus Proliferation10.1371/journal.ppat.1012872 ↗
16. Inhibition of Replication of Porcine Reproductive and respiratory Syndrome Virus by Hemin Is Highly Dependent on Heme Oxygenase‐1, but Independent of Iron in MARC‐145 Cells10.1016/j.antiviral.2014.02.010 ↗
17. Porcine Reproductive and respiratory Syndrome Virus Degrades DDX10 via SQSTM1/p62‐dependent Selective Autophagy to Antagonize Its Antiviral Activity10.1080/15548627.2023.2179844 ↗
18. Inhibitory Effect and Mechanism of Gelatin Stabilized Ferrous Sulfide Nanoparticles on Porcine Reproductive and respiratory Syndrome Virus10.1186/s12951-022-01281-4 ↗
19. Multi‐Omics Analysis by Machine Learning Identified Lysophosphatidic Acid as a Biomarker and Therapeutic Target for Porcine Reproductive and Respiratory Syndrome10.1002/advs.202402025 ↗
20. Iron Insertion at the Assembly Site of the ISCU Scaffold Protein Is a Conserved Process Initiating Fe–S Cluster Biosynthesis10.1021/jacs.2c06338 ↗
21. Evidence for [2Fe‐2S]2+ and Linear [3Fe‐4S]1+ Clusters in a Unique Family of Glycine/Cysteine‐Rich Fe‐S Proteins from Megavirinae Giant Viruses10.1021/jacs.2c10484 ↗
22. MMS19 links Cytoplasmic Iron‐sulfur Cluster Assembly to DNA Metabolism10.1126/science.1219664 ↗
23. Assessing the in Vitro and in Vivo Performance of L‐Carnitine‐Loaded Nanoparticles in Combating Obesity10.3390/molecules28207115 ↗
24. n Emerging Perspective
25. Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Antiangina Drug Perhexiline10.1038/onc.2016.103 ↗
26. Investigation on Host Susceptibility of Tibetan Pig to Infection of Porcine Reproductive and respiratory Syndrome Virus through Viral Challenge Study10.1016/j.vetmic.2015.11.035 ↗
27. Differences of Immune Responses Between Tongcheng (Chinese Local Breed) and Large White Pigs after Artificial Infection with Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus10.1016/j.virusres.2016.02.004 ↗
28. Molecular Characterization of Transcriptome‐wide Interactions Between Highly Pathogenic Porcine Reproductive and respiratory Syndrome Virus and Porcine Alveolar Macrophages in Vivo10.7150/ijbs.7.947 ↗
29. Integrated Time‐series Transcriptomic and Metabolomic Analyses Reveal Different Inflammatory and Adaptive Immune Responses Contributing to Host Resistance to PRRSV10.3389/fimmu.2022.960709 ↗
30. Ferroptosis and Ferritinophagy in Diabetes Complications10.1016/j.molmet.2022.101470 ↗
31. Human Cytomegalovirus Protein pUL38 Prevents Premature Cell Death by Binding to Ubiquitin‐Specific Protease 24 and Regulating Iron Metabolism
32. Human Parainfluenza Virus Type 2 V Protein Modulates Iron Homeostasis10.1128/JVI.01861-20 ↗
33. MMS19 assembles Iron‐sulfur Proteins Required for DNA Metabolism and Genomic Integrity10.1126/science.1219723 ↗
34. NCOA4‐Mediated Ferritinophagy Is a Pancreatic Cancer Dependency via Maintenance of Iron Bioavailability for Iron–Sulfur Cluster Proteins10.1158/2159-8290.CD-22-0043 ↗
35. NFS1 undergoes Positive Selection in Lung Tumours and Protects Cells from Ferroptosis10.1038/nature24637 ↗
36. Iron‐Sulfur Cluster Biogenesis as a Critical Target in Cancer10.3390/antiox10091458 ↗
37. Mechanisms of Mitochondrial Iron‐Sulfur Protein Biogenesis10.1146/annurev-biochem-013118-111540 ↗
38. Fe‐S Cluster Biogenesis in Isolated Mammalian Mitochondria10.1074/jbc.M114.610402 ↗
39. Mitochondrial Aconitase Controls Adipogenesis through Mediation of Cellular ATP Production10.1096/fj.201903224RR ↗
40. The Role of Lipids in Cancer Progression and Metastasis10.1016/j.cmet.2022.09.023 ↗
41. Acute Loss of Iron–sulfur Clusters Results in Metabolic Reprogramming and Generation of Lipid Droplets in Mammalian Cells10.1074/jbc.RA118.001885 ↗
42. STEAP3 Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication by Regulating Fatty Acid and Lipid Droplet Synthesis
43. Chitosan‐Coated Selenium Nanoparticles Attenuate PRRSV Replication and ROS/JNK‐Mediated Apoptosis in Vitro10.2147/IJN.S370585 ↗
44. TRIM46 accelerates H1N1 Influenza Virus‐induced Ferroptosis and Inflammatory Response by Regulating SLC7A11 Ubiquitination10.1007/s10863-024-10043-w ↗
45. Carnitine Biosynthesis. Beta‐Hydroxylation of Trimethyllysine by an Alpha‐ketoglutarate‐dependent Mitochondrial Dioxygenase10.1016/S0021-9258(17)34915-3 ↗
46. Carnitine Biosynthesis in Mammals10.1042/bj3610417 ↗
47. Alnustone Ameliorates Metabolic Dysfunction‐Associated Steatotic Liver Disease by Facilitating Mitochondrial Fatty Acid β‐Oxidation via Targeting Calmodulin10.1002/advs.202411984 ↗
48. ER‐Golgi‐localized Proteins TMED2 and TMED10 Control the Formation of Plasma Membrane Lipid Nanodomains10.1016/j.devcel.2022.09.004 ↗
49. HDLBP‐stabilized lncFAL Inhibits Ferroptosis Vulnerability by Diminishing Trim69‐dependent FSP1 Degradation in Hepatocellular Carcinoma10.1016/j.redox.2022.102546 ↗
50. Analysis of Biogenesis of Lipid Droplets by Examining Rab40c Associating with Lipid Droplets10.1007/978-1-4939-2309-0_10 ↗
51. The Lipid Droplet Is an Important Organelle for hepatitis C Virus Production10.1038/ncb1631 ↗
52. Dengue Virus Capsid Protein Usurps Lipid Droplets for Viral Particle Formation10.1371/journal.ppat.1000632 ↗
53. OCTN2 Enhances PGC‐1α‐mediated Fatty Acid Oxidation and OXPHOS to Support Stemness in Hepatocellular Carcinoma10.1016/j.metabol.2023.155628 ↗
54. Pseudorabies Virus Induces Ferroptosis by Disrupting Iron Homeostasis through Activation of TfR1 and Ferritinophagy
55. Involvement of PRRSV NSP3 and NSP5 in the Autophagy Process10.1186/s12985-019-1116-x ↗
56. Cholesterol‐dependent Nsp5‐endosomes co‐trafficking to Lysosomes Facilitates Porcine Reproductive and respiratory Syndrome Virus Replication by Activating Autophagy10.1016/j.vetmic.2025.110507 ↗
57. The Exploitation of Host Autophagy and Ubiquitin Machinery by Mycobacterium Tuberculosis in Shaping Immune Responses and Host Defense during Infection10.1080/15548627.2021.2021495 ↗
58. Branching out: Improved Signaling by Heterotypic Ubiquitin Chains10.1016/j.tcb.2019.06.003 ↗