Activation of innate immunity by mitochondrial dsRNA in mouse cells lacking p53 protein

WIATREK-MOUMOULIDIS, Dagmara Marta, Maria Elena CANDELA, Jiří SEDMÍK, Jan OPPELT, Liam KEEGAN and Mary Anne O'CONNELL. Activation of innate immunity by mitochondrial dsRNA in mouse cells lacking p53 protein. RNA. Cold Spring Harbor: Cold Spring Harbor Laboratory Press, 2019, vol. 25, No 6, p. 713-726. ISSN 1355-8382. Available from: https://dx.doi.org/10.1261/rna.069625.118.

Basic information

• Original name: Activation of innate immunity by mitochondrial dsRNA in mouse cells lacking p53 protein
• Authors: WIATREK-MOUMOULIDIS, Dagmara Marta (616 Poland, belonging to the institution), Maria Elena CANDELA (380 Italy, belonging to the institution), Jiří SEDMÍK (203 Czech Republic, belonging to the institution), Jan OPPELT (203 Czech Republic, belonging to the institution), Liam KEEGAN (372 Ireland, belonging to the institution) and Mary Anne O'CONNELL (372 Ireland, guarantor, belonging to the institution).
• Edition: RNA, Cold Spring Harbor, Cold Spring Harbor Laboratory Press, 2019, 1355-8382.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 10608 Biochemistry and molecular biology
• Country of publisher: United States of America
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 4.320
• RIV identification code: RIV/00216224:14740/19:00109412
• Organization unit: Central European Institute of Technology
• Doi: http://dx.doi.org/10.1261/rna.069625.118
• UT WoS: 000468092200005
• Keywords in English: mitochondrial dsRNA; p53; innate immunity; RNase L
• Tags: CF BIOIT, CF GEN, rivok
• Tags: International impact, Reviewed

Abstract

Viral and cellular double-stranded RNA (dsRNA) is recognized by cytosolic innate immune sensors, including RIG-I-like receptors. Some cytoplasmic dsRNA is commonly present in cells, and one source is mitochondrial dsRNA, which results from bidirectional transcription of mitochondrial DNA (mtDNA). Here we demonstrate that Trp53 mutant mouse embryonic fibroblasts contain immune-stimulating endogenous dsRNA of mitochondrial origin. We show that the immune response induced by this dsRNA is mediated via RIG-I-like receptors and leads to the expression of type I interferon and proinflammatory cytokine genes. The mitochondrial dsRNA is cleaved by RNase L, which cleaves all cellular RNA including mitochondrial mRNAs, increasing activation of RIG-I-like receptors. When mitochondrial transcription is interrupted there is a subsequent decrease in this immune-stimulatory dsRNA. Our results reveal that the role of p53 in innate immunity is even more versatile and complex than previously anticipated. Our study, therefore, sheds new light on the role of endogenous RNA in diseases featuring aberrant immune responses.

Links

• LM2015091, research and development project: Name: Národní centrum lékařské genomiky (Acronym: NCLG)

Investor: Ministry of Education, Youth and Sports of the CR

• 621368, interní kód MU: Name: The ERA Chair Culture as a Catalyst to Maximize the Potential of CEITEC (Acronym: CEITEC_ERA)

Investor: European Union, The ERA Chair Culture as a Catalyst to Maximize the Potential of CEITEC, Capacities