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SAMHD1 controls innate immunity by regulating condensation of immunogenic self RNA

Item Type:Article
Title:SAMHD1 controls innate immunity by regulating condensation of immunogenic self RNA
Creators Name:Maharana, S. and Kretschmer, S. and Hunger, S. and Yan, X. and Kuster, D. and Traikov, S. and Zillinger, T. and Gentzel, M. and Elangovan, S. and Dasgupta, P. and Chappidi, N. and Lucas, N. and Maser, K.I. and Maatz, H. and Rapp, A. and Marchand, V. and Chang, Y.T. and Motorin, Y. and Hubner, N. and Hartmann, G. and Hyman, A.A. and Alberti, S. and Lee-Kirsch, M.A.
Abstract:Recognition of pathogen-derived foreign nucleic acids is central to innate immune defense. This requires discrimination between structurally highly similar self and nonself nucleic acids to avoid aberrant inflammatory responses as in the autoinflammatory disorder Aicardi-Goutières syndrome (AGS). How vast amounts of self RNA are shielded from immune recognition to prevent autoinflammation is not fully understood. Here, we show that human SAM-domain- and HD-domain-containing protein 1 (SAMHD1), one of the AGS-causing genes, functions as a single-stranded RNA (ssRNA) 3'exonuclease, the lack of which causes cellular RNA accumulation. Increased ssRNA in cells leads to dissolution of RNA-protein condensates, which sequester immunogenic double-stranded RNA (dsRNA). Release of sequestered dsRNA from condensates triggers activation of antiviral type I interferon via retinoic-acid-inducible gene I-like receptors. Our results establish SAMHD1 as a key regulator of cellular RNA homeostasis and demonstrate that buffering of immunogenic self RNA by condensates regulates innate immune responses.
Keywords:SAMHD1, Type I Interferon, Aicardi-Goutières Syndrome, Condensate, Phase Separation, RNA, Innate Immunity, Autoinflammation, dsRNA, Stress Granules
Source:Molecular Cell
ISSN:1097-2765
Publisher:Cell Press
Volume:82
Number:19
Page Range:3712-3728.e10
Date:6 October 2022
Official Publication:https://doi.org/10.1016/j.molcel.2022.08.031
PubMed:View item in PubMed

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