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RNA-binding proteins hnRNPM and ELAVL1 promote type-I interferon induction downstream of the nucleic acid sensors cGAS and RIG-I

ABSTRACT: RIG-I like helicases (RLHs) and cGAS are crucial cytosolic sensors of viral RNA and DNA, respectively, and induce type I IFNs via TBK1/IKKε. hnRNPM was described to possess antimicrobial activities. Here, we show that hnRNPM promotes IRF3 phosphorylation and type I IFN induction downstream of cGAS and RIG-I in THP-1 cells and primary human fibroblasts. Interactome analysis revealed that hnRNPM forms a multiprotein complex with ELAVL1, TBK1, IKKε, IKKβ, and NF-κB p65. hnRNPM, ELAVL1, and TBK1 predominantly interacted in the cytosol. To our knowledge, hnRNPM and ELAVL1 represent the first non-redundant signaling components merging the cGAS-STING and RIG-I–MAVS pathways. Therefore, our findings may have implications for host defense and auto-inflammatory diseases.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Christian Urban

LAB HEAD: Andreas Pichlmair

PROVIDER: PXD028160 | Pride | 2024-11-11

REPOSITORIES: pride

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			Action	DRS
	20201016_QEp5_AnPi_SA_ELAVL1-GFP_1.raw	Raw
	20201016_QEp5_AnPi_SA_ELAVL1-GFP_2.raw	Raw
	20201016_QEp5_AnPi_SA_ELAVL1-GFP_3.raw	Raw
	20201016_QEp5_AnPi_SA_ELAVL1-GFP_4.raw	Raw
	20201016_QEp5_AnPi_SA_GFP_1.raw	Raw

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RNA-binding proteins hnRNPM and ELAVL1 promote type-I interferon induction downstream of the nucleic acid sensors cGAS and RIG-I

Project description:RIG-I like helicases (RLHs) and cGAS are crucial cytosolic sensors of viral RNA and DNA, respectively, and induce type I IFNs via TBK1/IKKε. hnRNPM was described to possess antimicrobial activities. Here, we show that hnRNPM promotes IRF3 phosphorylation and type I IFN induction downstream of cGAS and RIG-I in THP-1 cells and primary human fibroblasts. Interactome analysis revealed that hnRNPM forms a multiprotein complex with ELAVL1, TBK1, IKKε, IKKβ, and NF-κB p65. hnRNPM, ELAVL1, and TBK1 predominantly interacted in the cytosol. To our knowledge, hnRNPM and ELAVL1 represent the first non-redundant signaling components merging the cGAS-STING and RIG-I–MAVS pathways. Therefore, our findings may have implications for host defense and auto-inflammatory diseases.

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RNA-binding proteins hnRNPM and ELAVL1 promote type-I interferon induction downstream of the nucleic acid sensors cGAS and RIG-I

Project description:RNA-binding proteins hnRNPM and ELAVL1 promote type-I interferon induction downstream of the nucleic acid sensors cGAS and RIG-I

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Identification of cGAS acetylation and phosphorylation

Project description:DNA derived from the genetic material of pathogens or from cellular DNA damage provides a molecular pattern that can be sensed by pattern-recognition receptors of the mammalian innate immune system. In recent years, the cyclic GMP-AMP synthase (cGAS) protein has been characterized as a primary cytosolic DNA sensor during infection with bacteria, DNA viruses, or retroviruses. While the role of cGAS in downstream immune signaling through STING-TBK1-IRF3 proteins is well-defined, regulatory mechanisms of cGAS activity, such as through post-translational modifications (PTMs), are still an active area of research. Here, we report a comprehensive characterization of cGAS phosphorylations and acetylations in three different cell types. Data-dependent proteomic analyses of immunoaffinity purified cGAS was performed in HEK293T cells under control and DNA-challenged conditions (N = 3 each) and human fibroblasts (HFF) cells under control and HSV-1 infected conditions (N = 4 each) to generate candidate cGAS PTM sites. Using parallel reaction monitoring, a total of 11 PTMs (4 phosphorylations and 7 acetylations) were validated in HEK293T, HFF, and THP-1 cells. Of these, 3 phosphorylations and 5 acetylations have not been previously identified. The functions of these modifications were by generating a series of mutants and measuring cGAS-dependent apoptotic and immune signaling activities.

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