The 4EHP-mediated translational repression of cGAS impedes the host immune response against DNA viruses.

Autor:	Ladak RJ; Department of Biochemistry, Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada., Choi JH; Department of Biochemistry, Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada., Luo J; Department of Biochemistry, Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada., Chen OJ; Department of Biochemistry, Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada., Mahmood N; Department of Biochemistry, Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada., He AJ; Department of Physiology, McGill University, Montreal, QC H3A 1A2, Canada., Naeli P; Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast BT9 7AE, United Kingdom., Snell PH; Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast BT9 7AE, United Kingdom., Bayani E; Department of Ophthalmology and Visual Sciences, McGill University, Montreal, QC H3A 2B4, Canada., Hoang HD; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada., Alain T; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada., Teodoro JG; Department of Biochemistry, Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada., Wang J; Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China., Zhang X; Department of Biochemistry, Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada., Jafarnejad SM; Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast BT9 7AE, United Kingdom., Sonenberg N; Department of Biochemistry, Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Nov 26; Vol. 121 (48), pp. e2413018121. Date of Electronic Publication: 2024 Nov 19.
DOI:	10.1073/pnas.2413018121
Abstrakt:	A critical host response against viral infections entails the activation of innate immune signaling that culminates in the production of antiviral proteins. DNA viruses are sensed by the cytosolic pattern recognition receptor cyclic GMP-AMP synthase (cGAS), which initiates a signaling pathway that results in production of proinflammatory cytokines such as Interferon-β (IFN-β) and activation of the antiviral response. Precise regulation of the antiviral innate immune response is required to avoid deleterious effects of its overactivation. We previously reported that the 4EHP/GIGYF2 translational repressor complex reduces the translation of Ifnb1 mRNA, which encodes IFN-β, upon RNA viral infections. Here, we report a distinct regulatory mechanism by which 4EHP controls replication of DNA viruses by translational repression of the Cgas mRNA, which encodes the DNA viral sensor cGAS. We show that 4EHP is required for effective translational repression of Cgas mRNA triggered by miR-23a. Upon infection, 4EHP deficiency bolsters the elicited innate immune response against the diverse DNA viruses Herpes simplex virus 1 (HSV-1) and Vaccinia Virus (VacV) and concomitantly reduces their rate of replication in vitro and in vivo. This study elucidates an intrinsic regulatory mechanism of the host response to DNA viruses which may provide unique opportunities for countering viral infections. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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