tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2026 Mar 24;123(12):e2522111123.
doi: 10.1073/pnas.2522111123. Epub 2026 Mar 16.
Defective RNA Polymerase III sensing of mitochondrial DNA in pulmonary epithelial cells impairs type I IFN immunity to SARS-CoV-2
Michelle Møhlenberg[SUP] #[/SUP][SUP] 1 2 [/SUP], Sofie Eg Jørgensen[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Renée Marije van der Sluis[SUP] 1 2 [/SUP], Thomas Zillinger[SUP] 1 2 4 [/SUP], Daniëla Maria Hinke[SUP] 1 2 [/SUP], Anne Kruse Hollensen[SUP] 1 [/SUP], Anne Louise Hansen[SUP] 1 [/SUP]; COVID Human genetic Effort; Danish COVID-19 clinicians; COVID-19 DNABR Group; French COVID Cohort Study Group; COVIDeF Study Group; CoV-Contact Cohort; COVID-STORM Clinicians; Amsterdam UMC COVID-19 Biobank; NIAID-USUHS COVID Study Group; Pierre Hausfater[SUP] 5 [/SUP], Guy Gorochov[SUP] 5 [/SUP], Florence Tubach[SUP] 5 [/SUP], Jade Ghosn[SUP] 6 [/SUP], Cedric Laouenan[SUP] 6 [/SUP], Merete Storgaard[SUP] 3 [/SUP], Christian Kanstrup Holm[SUP] 1 [/SUP], Helen Su[SUP] 7 [/SUP], Rebeca Pérez de Diego[SUP] 8 [/SUP], Aurora Pujol[SUP] 9 10 11 [/SUP], Shen-Ying Zhang[SUP] 12 13 14 [/SUP], Qian Zhang[SUP] 12 13 14 [/SUP], Fernanda Sales Luiz Vianna[SUP] 15 16 [/SUP], Laurent Abel[SUP] 12 13 14 [/SUP], Aurélie Cobat[SUP] 12 13 14 [/SUP], Jean-Laurent Casanova[SUP] 12 13 14 17 18 [/SUP], Trine H Mogensen[SUP] 1 2 3 [/SUP]
Affiliations
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 POLR3A and POLR3C 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.
Keywords: COVID-19; RNA polymerase III; inborn errors of immunity; interferon; mitocholdrial DNA.
. 2026 Mar 24;123(12):e2522111123.
doi: 10.1073/pnas.2522111123. Epub 2026 Mar 16.
Defective RNA Polymerase III sensing of mitochondrial DNA in pulmonary epithelial cells impairs type I IFN immunity to SARS-CoV-2
Michelle Møhlenberg[SUP] #[/SUP][SUP] 1 2 [/SUP], Sofie Eg Jørgensen[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Renée Marije van der Sluis[SUP] 1 2 [/SUP], Thomas Zillinger[SUP] 1 2 4 [/SUP], Daniëla Maria Hinke[SUP] 1 2 [/SUP], Anne Kruse Hollensen[SUP] 1 [/SUP], Anne Louise Hansen[SUP] 1 [/SUP]; COVID Human genetic Effort; Danish COVID-19 clinicians; COVID-19 DNABR Group; French COVID Cohort Study Group; COVIDeF Study Group; CoV-Contact Cohort; COVID-STORM Clinicians; Amsterdam UMC COVID-19 Biobank; NIAID-USUHS COVID Study Group; Pierre Hausfater[SUP] 5 [/SUP], Guy Gorochov[SUP] 5 [/SUP], Florence Tubach[SUP] 5 [/SUP], Jade Ghosn[SUP] 6 [/SUP], Cedric Laouenan[SUP] 6 [/SUP], Merete Storgaard[SUP] 3 [/SUP], Christian Kanstrup Holm[SUP] 1 [/SUP], Helen Su[SUP] 7 [/SUP], Rebeca Pérez de Diego[SUP] 8 [/SUP], Aurora Pujol[SUP] 9 10 11 [/SUP], Shen-Ying Zhang[SUP] 12 13 14 [/SUP], Qian Zhang[SUP] 12 13 14 [/SUP], Fernanda Sales Luiz Vianna[SUP] 15 16 [/SUP], Laurent Abel[SUP] 12 13 14 [/SUP], Aurélie Cobat[SUP] 12 13 14 [/SUP], Jean-Laurent Casanova[SUP] 12 13 14 17 18 [/SUP], Trine H Mogensen[SUP] 1 2 3 [/SUP]
Affiliations
- PMID: 41838921
- DOI: 10.1073/pnas.2522111123
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 POLR3A and POLR3C 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.
Keywords: COVID-19; RNA polymerase III; inborn errors of immunity; interferon; mitocholdrial DNA.