Journal article
Mitochondrial targeting by measles virus nucleoprotein modulates viral spread in human airway epithelium
PLoS pathogens, Vol.21(11), e1013713
11/20/2025
DOI: 10.1371/journal.ppat.1013713
PMCID: PMC12646431
PMID: 41264643
Abstract
Measles is the most infectious human respiratory virus: on average, one individual with measles infects 12-18 susceptible people in a population without immunity. However, how measles virus (MeV) establishes infection in the human respiratory epithelium is insufficiently understood. Since our analyses of MeV infections of well-differentiated primary human airway epithelial cells (HAE) revealed perturbations of mitochondrial gene expression, we tested mitochondrial function. MeV replication disrupted mitochondrial membrane potential and induced superoxide production. This resulted in cGAS-dependent interferon-stimulated gene expression without interferon induction. We then assessed by differential centrifugation whether MeV replicates in mitochondrial proximity. Indeed, MeV proteins and genome were enriched in mitochondrial fractions. We identified a previously unrecognized potential mitochondrial localization signal (MLS) in the MeV nucleoprotein (N), the first protein expressed during infection and showed that the first 70 amino acids of N are sufficient to deliver a GFP reporter to mitochondria. Mutational analyses revealed that arginine 6 and arginine 13 of the N protein are critical for targeting. Recombinant MeV mutants harboring single MLS amino acid substitutions exhibited altered replication kinetics and infectious center formation in HAE, despite similar ISG expression profiles to wild-type MeV. Thus, the MeV N protein amino-terminal arm, previously known only to promote formation of the helical ribonucleocapsid protecting the viral genome, also codes for an MLS. In newly infected cells, this signal may target the formation of MeV replication factories near mitochondria without provoking a canonical RNA sensing pathway. Notably, the MLS appears unique to Morbillivirus N proteins within the Paramyxoviridae family, which are also distinguished by the unique ability to form infectious centers in HAE. Our findings reveal a novel mechanism by which MeV exploits mitochondrial proximity to coordinate replication and modulate host responses, offering new insights into virus-host interactions at the organelle level.
Details
- Title: Subtitle
- Mitochondrial targeting by measles virus nucleoprotein modulates viral spread in human airway epithelium
- Creators
- Lorellin A Durnell-Bettis - Department of Microbiology and Immunology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of AmericaStephanie E Clark - University of IowaCamilla E Hippee - University of IowaAngela Liu - Department of Microbiology and Immunology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of AmericaJustin W Kaufman - University of IowaSydney R Winecke - Department of Microbiology and Immunology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of AmericaKalpana Yadav - Mayo ClinicBrajesh K Singh - University of IowaRoberto Cattaneo - Mayo ClinicPatrick L Sinn - Stead Family Department of Pediatrics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America
- Resource Type
- Journal article
- Publication Details
- PLoS pathogens, Vol.21(11), e1013713
- DOI
- 10.1371/journal.ppat.1013713
- PMID
- 41264643
- PMCID
- PMC12646431
- NLM abbreviation
- PLoS Pathog
- ISSN
- 1553-7374
- eISSN
- 1553-7374
- Publisher
- PLOS
- Grant note
- National Institutes of Health: T32 AL007533 Division of Intramural Research, National Institute of Allergy and Infectious Diseases: R01 AI189662
This work was supported by the National Institutes of Health: NIH R01 AI189662 (PLS) and R21 AI187987 (BKS), and T32 AL007533. The funders played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- Language
- English
- Date published
- 11/20/2025
- Academic Unit
- Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics
- Record Identifier
- 9985033873702771
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