Evidence map›Paper›PMID 42287635›Full record

ArticleCell reports2026

SARS-CoV-2 ORF3a blocks lysosomal cholesterol egress by disrupting VPS39-regulated NPC2 trafficking and BMP metabolism.

Baley A Goodson, Valeria Montenegro Vazquez, Aliza Doyle, Oralia M Kolaczkowski, Rui Liu, Jingyue Jia, Morié Ishida, Chunyan Ye, Alison M Kell, Steven B Bradfute and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

14 authors.

Baley A GoodsonDepartment of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Valeria Montenegro VazquezDepartment of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Aliza DoyleDepartment of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Oralia M KolaczkowskiDepartment of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Rui LiuDepartment of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Jingyue JiaDepartment of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Morié IshidaNeurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Chunyan YeDepartment of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Alison M KellDepartment of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Steven B BradfuteDepartment of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Monica Rosas LemusDepartment of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Hu WangDepartment of Medicine, UT Health San Antonio Long School of Medicine, San Antonio, TX, USA.
Xianlin HanDepartment of Medicine, UT Health San Antonio Long School of Medicine, San Antonio, TX, USA.
Jing PuDepartment of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA. Electronic address: jpu@salud.unm.edu.

Funding

TRANSGENIC COREP30AG013319 · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 1995 to 2025
$7.5M
WOMEN'S CANCERS RESEARCH PROGRAMP30CA118100 · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2005 to 2025
$3.9M
Science CoreP20GM121176 · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2025 to 2025
$2.2M
Initiative to Maximize Student Diversity at the University of New Mexico Health Sciences Center 2021T32GM144834 · NIGMS · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2023 to 2025
$1.1M
Lysosome‐Lipid Droplet Interactions in Fatty Acid MetabolismR35GM147419 · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2025 to 2025
$381k
NCI NIH HHS P30 CA118100NIA NIH HHS P30 AG013319NIGMS NIH HHS P20 GM121176NIGMS NIH HHS R35 GM147419NIGMS NIH HHS T32 GM144834
6 · The paper itself

Abstract

Cholesterol homeostasis depends on lysosomes liberating cholesterol from degraded lipids. We show that SARS-CoV-2 blocks lysosomal cholesterol egress through the viral protein ORF3a. ORF3a binds the HOPS subunit VPS39 via the W193 and Y184 residues. Disrupting this interface restores cholesterol trafficking. Mechanistically, the ORF3a-VPS39 interaction exerts dual effects. First, it traps the retromer complex on endolysosomes, preventing endosome-to-Golgi recycling and mislocalizing the cholesterol transporter NPC2. Retromer deletion reproduced these defects, whereas the ORF3a W193A mutant restored retromer trafficking. Second, ORF3a-VPS39 interaction reduces bis(monoacylglycerol)phosphates (BMPs), lysosomal lipids required for cholesterol egress, by disrupting the transfer of their precursor, phosphatidylglycerols, from mitochondria. Lipidomics revealed increased mitochondrial and decreased lysosomal phosphatidylglycerol metabolites. Disturbing autophagy or mitochondrion-derived vesicles did not alter BMP levels, whereas ORF3a reduced mitochondrion-lysosome membrane contacts. These findings identify dual functions of VPS39-regulating retromer trafficking and BMP biosynthesis-and also reveal how ORF3a blocks lysosomal cholesterol egress.

Indexed as

Carrier ProteinsCholesterolCOVID-19GlycoproteinsLysosomesMonoglyceridesSARS-CoV-2Vesicular Transport ProteinsViroporin ProteinsBiological TransportEndosomesHeLa CellsHumansLysophospholipidsMitochondriaProtein Transportbis(monoacylglyceryl)phosphateCarrier ProteinsCholesterolGlycoproteinsLysophospholipidsMonoglyceridesNPC2 protein, humanORF3a protein, SARS-CoV-2Vesicular Transport ProteinsViroporin Proteinsbis(monoacylglycero)phosphatesBMPscellular cholesterol transportCP: cell biologyCP: microbiologyHOPSlysosome-mitochondrion interactionsretromer

Identifiers

PMID42287635
PMCPMC13378056

What Socratic holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.