Defective RNA Polymerase III sensing of mitochondrial DNA in pulmonary epithelial cells impairs type I IFN immunity to SARS-CoV-2

The clinical spectrum of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection ranges from asymptomatic cases to critical COVID-19 pneumonia. To investigate the role of host genetics in susceptibility to critical COVID-19 and identify pathophysiological mechanisms and pathways, we analyzed whole-exome and whole-genome sequencing data from the COVID Human Genetic Effort. We identified 10 rare, monoallelic predicted loss-of-function variants in 18 patients in <i>POLR3A</i> and <i>POLR3C</i> encoding two subunits of RNA polymerase III (POL III), a nuclear multisubunit enzyme, which has been implicated in cytosolic DNA sensing. These variants were deleterious for expression of full-length POLR3A and POLR3C proteins. We demonstrate that human pulmonary A549-hACE2 cells with reduced POLR3A or POLR3C expression exhibit impaired type I IFN responses to transfected mitochondrial DNA (mtDNA) or SARS-CoV-2 infection, together with increased viral replication. Mechanistically, we show that SARS-CoV-2 induces cellular mtDNA release via oligomerization of the mitochondrial voltage-dependent anion channel under virus-induced oxidative stress, enabling POL III-mtDNA interaction. These findings establish POL III as a sensor of endogenous mtDNA released during viral infection and indicate that autosomal dominant POL III haploinsufficiency may predispose individuals to critical COVID-19.

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Journal
Proceedings of the National Academy of Sciences
Published
2026-03-16
DOI
https://doi.org/10.1073/pnas.2522111123
Primary Topic
interferon and immune responses
Type
article
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article

Defective RNA Polymerase III sensing of mitochondrial DNA in pulmonary epithelial cells impairs type I IFN immunity to SARS-CoV-2

Rebeca Pérez de Diego, Daniëla Maria Hinke, Fernanda Sales Luiz Vianna, Sofie E. Jørgensen et al.
Proceedings of the National Academy of Sciences
interferon and immune responses
article

Defective RNA Polymerase III sensing of mitochondrial DNA in pulmonary epithelial cells impairs type I IFN immunity to SARS-CoV-2

Rebeca Pérez de Diego, Daniëla Maria Hinke, Fernanda Sales Luiz Vianna, Sofie E. Jørgensen, Pierre Hausfater, Florence Tubach, Q. Zhang, Hua Su, Thomas Zillinger, Laurent Abel, CoV-Contact Cohort, French COVID Cohort Study Group, Shen-Ying Zhang, CHRISTIAN KANSTRUP HOLM, Jade Ghosn, Cedric Laouenan, Michelle Møhlenberg, Anne Kruse Hollensen, Anne Louise Hansen, Trine H. Mogensen, Jean-Laurent Casanova, Aurora Pujol, NIAID-USUHS COVID Study Group, Guy Gorochov, Merete Storgaard, COVIDeF Study Group, Amsterdam UMC COVID-19 Biobank, Aurélie Cobat, COVID Human genetic Effort, COVID-19 DNABR Group, Renée Marije van der Sluis
article en

Abstract

The clinical spectrum of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection ranges from asymptomatic cases to critical COVID-19 pneumonia. To investigate the role of host genetics in susceptibility to critical COVID-19 and identify pathophysiological mechanisms and pathways, we analyzed whole-exome and whole-genome sequencing data from the COVID Human Genetic Effort. We identified 10 rare, monoallelic predicted loss-of-function variants in 18 patients in <i>POLR3A</i> and <i>POLR3C</i> encoding two subunits of RNA polymerase III (POL III), a nuclear multisubunit enzyme, which has been implicated in cytosolic DNA sensing. These variants were deleterious for expression of full-length POLR3A and POLR3C proteins. We demonstrate that human pulmonary A549-hACE2 cells with reduced POLR3A or POLR3C expression exhibit impaired type I IFN responses to transfected mitochondrial DNA (mtDNA) or SARS-CoV-2 infection, together with increased viral replication. Mechanistically, we show that SARS-CoV-2 induces cellular mtDNA release via oligomerization of the mitochondrial voltage-dependent anion channel under virus-induced oxidative stress, enabling POL III-mtDNA interaction. These findings establish POL III as a sensor of endogenous mtDNA released during viral infection and indicate that autosomal dominant POL III haploinsufficiency may predispose individuals to critical COVID-19.

Proceedings of the National Academy of SciencesVol. 123(12)
Université Claude Bernard Lyon 1 (FR), Institució Catalana de Recerca i Estudis Avançats (ES), Universidade Federal do Rio Grande do Sul (BR), Inserm (FR), Aarhus University (DK), Université Paris Cité (FR), University Hospital Bonn (DE), Great Ormond Street Hospital (GB), Hospital for Sick Children (CA), Bellvitge University Hospital (ES), Aarhus University Hospital (DK), Sorbonne Université (FR), Hospital de Clínicas de Porto Alegre (BR), Hospital La Paz Institute for Health Research (ES), Centre for Biomedical Network Research on Rare Diseases (ES), Institute for Biomedicine (IT), Institut Pierre Louis d‘Épidémiologie et de Santé Publique (FR), National Institute of Allergy and Infectious Diseases (US), SickKids Foundation (CA), Hôpital Bichat-Claude-Bernard (FR), Institut des Maladies Génétiques Imagine (FR), Ekaterinburg Research Institute of Viral Infections (RU), University College London (GB), Rockefeller University (US), University of Rio Grande and Rio Grande Community College (US)
Good health and well-being
Openalex Percentile: Top 19%
interferon and immune responses
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