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We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI). We thank Montserrat Duque and Eva Merino for technical assistance. This work was supported by the Spanish Ministry of Economy, Industry, and Competitiveness (grant SAF2016-80883-R), Spanish Ministry of Science and Innovation (MICIN/AEI/10.13039/501100011033; grants PID2019-105989RB-I00; PID2020-116918RB-100; and PID2020-117425RB-C21), CIBERDEM-ISCIII (grant CB07/08/0004), and the Regional Government of Castile and Leon (grant CSI141P20, cofinanced by the European Union through the European Regional Development Fund, "A Way of Making Europe"). N. de Pablo and J. Martinez-Garcia were supported by predoctoral fellowships from the Spanish Ministry of Science and Innovation (FPU14-02879) and the Regional Government of Castile and Leon (E-47-2021-0015435), respectively. Instituto de Biologia y Genetica Molecular is a research center partnered between the Spanish National Research Council (CSIC) and the University of Valladolid.

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Lipin-2 regulates the antiviral and anti-inflammatory responses to interferon

Publicated to:EMBO REPORTS. 24 (12): e57238-e57238 - 2023-12-06 24(12), DOI: 10.15252/embr.202357238

Authors: de Pablo, N; Meana, C; Martínez-García, J; Martínez-Vicente, P; Albert, M; Guerra, S; Angulo, A; Balsinde, J; Balboa, MA

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Abstract

Interferons (IFN) are crucial antiviral and immunomodulatory cytokines that exert their function through the regulation of a myriad of genes, many of which are not yet characterized. Here, we reveal that lipin-2, a phosphatidic acid phosphatase whose mutations produce an autoinflammatory syndrome known as Majeed syndrome in humans, is regulated by IFN in a STAT-1-dependent manner. Lipin-2 inhibits viral replication both in vitro and in vivo. Moreover, lipin-2 also acts as a regulator of inflammation in a viral context by reducing the signaling through TLR3 and the generation of ROS and release of mtDNA that ultimately activate the NLRP3 inflammasome. Inhibitors of mtDNA release from mitochondria restrict IL-1β production in lipin-2-deficient animals in a model of viral infection. Finally, analyses of databases from COVID-19 patients show that LPIN2 expression levels negatively correlate with the severity of the disease. Overall, these results uncover novel regulatory mechanisms of the IFN response driven by lipin-2 and open new perspectives for the future management of patients with LPIN2 mutations.© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

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