The ability of SAMHD1-deficient monocytes to trigger the Type I IFN response depends on cGAS and mitochondrial DNA
Abstract
In humans, mutations in sterile α motif and histidine-aspartate domain–containing protein 1 (SAMHD1) lead to the development of a type I interferonopathy known as Aicardi–Goutières syndrome (AGS). AGS can present with a variety of severe phenotypes in patients, and a hallmark of this disease is chronic activation of type I interferon (IFN) signaling. However, the mechanism through which type I IFN signaling is activated in the absence of functional SAMHD1 is not known. Here, we investigated the molecular pathways that lead to type I IFN signaling activation in the absence of SAMHD1. Our investigations revealed that chronic activation of type I IFN signaling in SAMHD1-knockout (KO) monocytes is cyclic GMP–AMP synthase (cGAS)-dependent. Analysis of other nucleic acid sensors showed that type I IFN signaling in SAMHD1-KO cells is not dependent on melanoma differentiation-associated protein 5 (MDA5) or retinoic acid–inducible gene I (RIG-I). In agreement with our observation that type I IFN signaling is dependent on cGAS, two inhibitors of the cGAS–stimulator of IFN genes pathway, G140 and H151, effectively prevented type I IFN activation in SAMHD1-KO monocytes. We also found that type I IFN signaling in SAMHD1-KO monocytes is dependent on type I IFN receptor expression. Further exploration revealed mitochondrial malfunction in SAMHD1-KO monocytes that is likely to leak mitochondrial components into the cytoplasm. Overall, our work suggests that genetic knock out of SAMHD1 leads to mitochondrial disfunction, resulting in the presence of mitochondrial DNA in the cytoplasm, which triggers cGAS and the type I IFN response.
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BibTeX
@article{rabinowitz2026ability,
title = {{The ability of SAMHD1-deficient monocytes to trigger the Type I IFN response depends on cGAS and mitochondrial DNA}},
author = {Jesse Rabinowitz and Isabelle Vila and Charlotte Luchsinger and Cinzia Bertelli and Moritz Schüssler and Clara Taffoni and Bin Cui and Annie Zhi Dai and Mohammad Rashid and William Cisneros and Daphne Cornish and Juan Redondo and Kathryn Jackson-Jones and Lacy Simons and Ramon Lorenzo-Redondo and Nadine Laguette and Judd Hultquist and Felipe Diaz-Griffero},
journal = {Journal of Biological Chemistry},
year = {2026},
month = sep,
doi = {10.1016/j.jbc.2025.110430},
url = {https://hal.science/hal-05362503v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The ability of SAMHD1-deficient monocytes to trigger the Type I IFN response depends on cGAS and mitochondrial DNA
AU - Jesse Rabinowitz
AU - Isabelle Vila
AU - Charlotte Luchsinger
AU - Cinzia Bertelli
AU - Moritz Schüssler
AU - Clara Taffoni
AU - Bin Cui
AU - Annie Zhi Dai
AU - Mohammad Rashid
AU - William Cisneros
AU - Daphne Cornish
AU - Juan Redondo
AU - Kathryn Jackson-Jones
AU - Lacy Simons
AU - Ramon Lorenzo-Redondo
AU - Nadine Laguette
AU - Judd Hultquist
AU - Felipe Diaz-Griffero
PY - 2026
DA - 2026/09/23
JO - Journal of Biological Chemistry
DO - 10.1016/j.jbc.2025.110430
UR - https://hal.science/hal-05362503v1
AB - In humans, mutations in sterile α motif and histidine-aspartate domain–containing protein 1 (SAMHD1) lead to the development of a type I interferonopathy known as Aicardi–Goutières syndrome (AGS). AGS can present with a variety of severe phenotypes in patients, and a hallmark of this disease is chronic activation of type I interferon (IFN) signaling. However, the mechanism through which type I IFN signaling is activated in the absence of functional SAMHD1 is not known. Here, we investigated the molecular pathways that lead to type I IFN signaling activation in the absence of SAMHD1. Our investigations revealed that chronic activation of type I IFN signaling in SAMHD1-knockout (KO) monocytes is cyclic GMP–AMP synthase (cGAS)-dependent. Analysis of other nucleic acid sensors showed that type I IFN signaling in SAMHD1-KO cells is not dependent on melanoma differentiation-associated protein 5 (MDA5) or retinoic acid–inducible gene I (RIG-I). In agreement with our observation that type I IFN signaling is dependent on cGAS, two inhibitors of the cGAS–stimulator of IFN genes pathway, G140 and H151, effectively prevented type I IFN activation in SAMHD1-KO monocytes. We also found that type I IFN signaling in SAMHD1-KO monocytes is dependent on type I IFN receptor expression. Further exploration revealed mitochondrial malfunction in SAMHD1-KO monocytes that is likely to leak mitochondrial components into the cytoplasm. Overall, our work suggests that genetic knock out of SAMHD1 leads to mitochondrial disfunction, resulting in the presence of mitochondrial DNA in the cytoplasm, which triggers cGAS and the type I IFN response.
SN - 0021-9258
SN - 1083-351X
ER -