23 mars 2023 à 11 h :

An isoform of Dicer protects mammalian stem cells against multiple RNA viruses

Enzo  POIRIER  –

Immunité et Cancer U932, Equipe Immunité des Cellules Souches, Institut Curie, Paris.

Abstract

Stem cells play a fundamental role in the maintenance of adult tissue architecture and must be shielded from viral infections. However, the protection conferred by the interferon pathway is severely compromised stem cells, which lack key components of the pathway. Despite this, stem cells are largely resistant to viruses, which can be attributed in part to the steady-state expression of interferon-stimulated genes. Nonetheless, immune responses in stem cells remain poorly characterised. In invertebrates and plants, antiviral immunity relies on RNA interference (RNAi), which is initiated by the cleavage of viral double-stranded RNA (dsRNA) by a Dicer protein. In mammals, a single Dicer gene has been described, which encodes a Dicer protein that cleaves dsRNA only poorly. Whether antiviral RNAi exists in mammalian cells remains highly controversial.

In this work, we identify a new Dicer isoform produced from the human and mouse Dicer gene that is better able to process dsRNA than canonical Dicer. This isoform, termed antiviral Dicer (aviD) is preferentially expressed in stem cells within adult tissues. Using a model of brain organoid infected with Zika virus or SARS-CoV-2, we demonstrate that aviD protects adult stem cells from RNA viruses by mounting a canonical antiviral RNAi response. This work highlights the composite nature of antiviral immunity in mammals, tailored to the differentiation status of the cell.

Bâtiment Jean Bernard

INSERM U944 UMR7212

Hôpital St Louis

16 rue de la Grange aux Belles

75010 PARIS

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