# SIRT4 regulates antiviral and autoimmune responses by promoting cGAS-mediated signaling pathways

## TL;DR

SIRT4 helps the body fight viruses and autoimmune issues by boosting cGAS activity, which detects DNA in cells.

## Contribution

SIRT4 is identified as a novel positive regulator of cGAS-mediated innate immune signaling.

## Key findings

- SIRT4 deacetylates cGAS, enhancing its interaction with DNA and boosting antiviral responses.
- SIRT4 deficiency or inhibition weakens innate immune signaling against DNA viruses and in autoimmune conditions like SLE.
- SIRT4 overexpression reduces HSV-1 infection, while its absence increases susceptibility.

## Abstract

Cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) is a critical cytosolic DNA sensor, whose activity can be regulated by acetylation. Here, we show that nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylase SIRT4 interacts with cGAS and positively regulates innate immune responses triggered by DNA viruses or cytoplasmic DNA. Overexpression of SIRT4 inhibits HSV-1 infection, whereas knockdown of SIRT4 has the opposite effect. Deficiency of SIRT4, or treatment with a SIRT4 inhibitor, impairs antiviral innate immune signaling in response to DNA viruses or cytoplasmic DNA, both in vitro and in vivo. Moreover, SIRT4 inhibitor treatment attenuates type I interferon signaling in Trex1-deficient cells and in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE). Mechanistically, SIRT4 deacetylates cGAS and enhances its association with double‑stranded DNA. Collectively, our study identifies SIRT4 as a positive regulator of cGAS-mediated innate immune signaling pathways, which advances the understanding of the regulation of cGAS activity.

Adenine dinucleotide (NAD + )-dependent lysine deacetylase SIRT4 interacts with cGAS and positively regulates innate immune signaling. SIRT4 deacetylates cGAS and promotes cGAS-mediated antiviral and autoimmune responses triggered by viral or cytoplasmic DNA.

SIRT4 interacts with and deacetylates cGAS, thus regulating virus- or cytoplasmic DNA-triggered innate immune responses.SIRT4 deficiency or specific inhibitor treatment results in impaired innate immune signaling in vitro and in vivo.SIRT4 inhibition attenuates the type I IFN signaling response in both Trex1-deficient cells and PBMCs from SLE patients.

SIRT4 interacts with and deacetylates cGAS, thus regulating virus- or cytoplasmic DNA-triggered innate immune responses.

SIRT4 deficiency or specific inhibitor treatment results in impaired innate immune signaling in vitro and in vivo.

SIRT4 inhibition attenuates the type I IFN signaling response in both Trex1-deficient cells and PBMCs from SLE patients.

Adenine dinucleotide (NAD + )-dependent lysine deacetylase SIRT4 interacts with cGAS and positively regulates innate immune signaling. SIRT4 deacetylates cGAS and promotes cGAS-mediated antiviral and autoimmune responses triggered by viral or cytoplasmic DNA.